Donald B. Katz

The EJC Factor eIF4AIII Modulates Synaptic Strength and Neuronal Protein Expression

Proper neuronal function and several forms of synaptic plasticity are highly dependent on precise control of mRNA translation, particularly in dendrites. We find that eIF4AIII, a core exon junction complex (EJC) component loaded onto mRNAs by pre-mRNA splicing, is associated with neuronal mRNA granules and dendritic mRNAs. eIF4AIII knockdown markedly increases both synaptic strength and GLUR1 AMPA receptor abundance at synapses. eIF4AIII depletion also increases ARC, a protein required for maintenance of long-term potentiation; arc mRNA, one of the most abundant in dendrites, is a natural target for nonsense-mediated decay (NMD). Numerous new NMD candidates, some with potential to affect synaptic activity, were also identified computationally. Two models are presented for how translation-dependent decay pathways such as NMD might advantageously function as critical brakes for protein synthesis in cells such as neurons that are highly dependent on spatially and temporally restricted protein expression.

Natural stimuli evoke dynamic sequences of states in sensory cortical ensembles

Although temporal coding is a frequent topic of neurophysiology research, trial-to-trial variability in temporal codes is typically dismissed as noise and thought to play no role in sensory function. Here, we show that much of this supposed “noise” faithfully reflects stimulus-related processes carried out in coherent neural networks. Cortical neurons responded to sensory stimuli by progressing through sequences of states, identifiable only in examinations of simultaneously recorded ensembles. The specific times at which ensembles transitioned from state to state varied from trial to trial, but the state sequences were reliable and stimulus-specific. Thus, the characterization of ensemble responses in terms of state sequences captured facets of sensory processing that are missing from, and obscured in, other analyses. This work provides evidence that sensory neurons act as parts of a systems-level dynamic process, the nature of which can best be appreciated through observation of distributed ensembles.

Firing Rate Homeostasis in Visual Cortex of Freely Behaving Rodents

It has been postulated that homeostatic mechanisms maintain stable circuit function by keeping neuronal firing within a set point range, but such firing rate homeostasis has never been demonstrated in vivo. Here we use chronic multielectrode recordings to monitor firing rates in visual cortex of freely behaving rats during chronic monocular visual deprivation (MD). Firing rates in V1 were suppressed over the first 2 day of MD but then rebounded to baseline over the next 2-3 days despite continued MD. This drop and rebound in firing was accompanied by bidirectional changes in mEPSC amplitude measured ex vivo. The rebound in firing was independent of sleep-wake state but was cell type specific, as putative FS and regular spiking neurons responded to MD with different time courses. These data establish that homeostatic mechanisms within the intact CNS act to stabilize neuronal firing rates in the face of sustained sensory perturbations.

The Impact of Audition on the Development of Visual Attention

Interactions between audition and vision were investigated in two experiments In the first experiment, school-age hearing children, deaf children with cochlear implants, and deaf children without implants participated in a task in which they were to respond to some visual signals and not others This task did not involve sound at all Deaf children without implants performed much more poorly than hearing children Deaf children with cochlear implants performed considerably better than deaf children without implants The second experiment employed a longitudinal design and showed that the rate of development in visual selective attention was faster for deaf children with cochlear implants than deaf children without implants Moreover, the gains were rapid—occurring within 2 years post-implant surgery The results suggest that a history of experience with sounds matters in the development of visual attention The results are discussed in terms of multimodal developmental processes

Gustatory processing is dynamic and distributed.

The process of gustatory coding consists of neural responses that provide information about the quantity and quality of food, its generalized sensation, its hedonic value, and whether it should be swallowed. Many of the models presently used to analyze gustatory signals are static in that they use the average neural firing rate as a measure of activity and are unimodal in the sense they are thought to only involve chemosensory information. We have recently elaborated upon a dynamic model of gustatory coding that involves interactions between neurons in single as well as in spatially separate, gustatory and somatosensory regions. We propose that the specifics of gustatory responses grow not only out of information ascending from taste receptor cells, but also from the cycling of information around a massively interconnected system.

Behavioral States, Network States, and Sensory Response Variability

We review data demonstrating that single-neuron sensory responses change with the states of the neural networks (indexed in terms of spectral properties of local field potentials) in which those neurons are embedded. We start with broad network changes--different levels of anesthesia and sleep--and then move to studies demonstrating that the sensory response plasticity associated with attention and experience can also be conceptualized as functions of network state changes. This leads naturally to the recent data that can be interpreted to suggest that even brief experience can change sensory responses via changes in network states and that trial-to-trial variability in sensory responses is a nonrandom function of network fluctuations, as well. We suggest that the CNS may have evolved specifically to deal with stimulus variability and that the coupling with network states may be central to sensory processing.

Learning-Related Plasticity of Temporal Coding in Simultaneously Recorded Amygdala–Cortical Ensembles

Emotional learning requires the coordinated action of neural populations in limbic and cortical networks. Here, we performed simultaneous extracellular recordings from gustatory cortical (GC) and basolateral amygdalar (BLA) neural ensembles as awake, behaving rats learned to dislike the taste of saccharin [via conditioned taste aversion (CTA)]. Learning-related changes in single-neuron sensory responses were observed in both regions, but the nature of the changes was region specific. In GC, most changes were restricted to relatively late aspects of the response (starting ∼1.0 s after stimulus administration), supporting our hypothesis that in this paradigm palatability-related information resides exclusively in later cortical responses. In contrast, and consistent with data suggesting the amygdalas primary role in judging stimulus palatability, CTA altered all components of BLA taste responses, including the earliest. Finally, learning caused dramatic increases in the functional connectivity (measured in terms of cross-correlation peak heights) between pairs of simultaneously recorded BLA and GC neurons, increases that were evident only during taste processing. Our simultaneous assays of the activity of single neurons in multiple relevant brain regions across learning suggest that the transmission of taste information through amygdala–cortical circuits plays a vital role in CTA memory formation.

Semantic facutation in aphasia: Effects of time and expectancy

Two auditory lexical decision semantic priming experiments were conducted to examine the extent to which the automaticcontrolled processing dichotomy can characterize lexical access deficits in Brocas and Wernickes aphasics. In Experiment 1, prime-target predictability was varied while the interval between prime and target (ISI) was held constant. In Experiment 2, ISI was varied while prime-target predictability was held constant. The pattern of semantic facilitation and inhibition results for Experiment 1 showed that Brocas aphasics were influenced by prime-target predictability, whereas Wernickes aphasics were not. In contrast in hperiment 2, manipulations of ISI at 150 and 2000 msec did not affect patterns of semantic facilitation for either Brocas or Wernickes aphasics. Taken together, the results of these two experiments suggest that Brocas aphasics use heuristic strategies more so than old and young normal subjects. In addition, they seem to have an automatic processing deficit affecting the level of activation of lexical entries, with a spared time course of activation. Wernickes aphasics show a pattern of results consistent with the view that automatic processing is unimpaired in these patients, while they fail to use heuristic strategies in these tasks.

NMDAR antagonist action in thalamus imposes delta oscillations on the hippocampus

Work on schizophrenia demonstrates the involvement of the hippocampus in the disease and points specifically to hyperactivity of CA1. Many symptoms of schizophrenia can be mimicked by N-methyl-d-aspartate receptor (NMDAR) antagonist; notably, delta frequency oscillations in the awake state are enhanced in schizophrenia, an abnormality that can be mimicked by NMDAR antagonist action in the thalamus. Given that CA1 receives input from the nucleus reuniens of the thalamus, we sought to determine whether an NMDAR antagonist in the thalamus can affect hippocampal processes. We found that a systemic NMDAR antagonist (ketamine; 50 mg/kg) increased the firing rate of cells in the reuniens and CA1 in awake rats. Furthermore, ketamine increased the power of delta oscillations in both structures. The thalamic origin of the change in hippocampal properties was demonstrated in three ways: 1) oscillations in the two structures were coherent; 2) the hippocampal changes induced by systematic ketamine were reduced by thalamic injection of muscimol; and 3) the hippocampal changes could be induced by local injection of ketamine into the thalamus. Lower doses of ketamine (20 mg/kg) did not evoke delta oscillations but did increase hippocampal gamma power, an effect not dependent on the thalamus. There are thus at least two mechanisms for ketamine action on the hippocampus: a low-dose mechanism that affects gamma through a nonthalamic mechanism and a high-dose mechanism that increases CA1 activity and delta oscillations as a result of input from the thalamus. Both mechanisms may be important in producing symptoms of schizophrenia.

Distinct Subtypes of Basolateral Amygdala Taste Neurons Reflect Palatability and Reward

The amygdala processes multiple, dissociable properties of sensory stimuli. Given its central location within a dense network of reciprocally connected regions, it is reasonable to expect that basolateral amygdala (BLA) neurons should produce a rich repertoire of dynamical responses to taste stimuli. Here, we examined single BLA neuron taste responses in awake rats and report the existence of two distinct subgroups of BLA taste neurons operating simultaneously during perceptual processing. One neuron type produced long, protracted responses with dynamics that were strikingly similar to those previously observed in gustatory cortex. These responses reflect cooperation between amygdala and cortex for the purposes of processing palatability. A second type of BLA taste neuron may be part of the system often described as being responsible for reward learning: these neurons produced very brief, short-latency responses to rewarding stimuli; when the rat participated in procuring the taste by pressing a lever in response to a tone, however, those phasic taste responses vanished, phasic responses to the tone appearing instead. Our data provide strong evidence that the neural handling of taste is actually a distributed set of processes and that BLA is a nexus of these multiple processes. These results offer new insights into how amygdala imbues naturalistic sensory stimuli with value.