Glutamate dehydrogenase deficiency disrupts glutamate homeostasis in hippocampus and prefrontal cortex and impairs recognition memory

Glutamate Dehydrogenase 1 (GDH), encoded by the Glud1 gene in rodents, is a mitochondrial enzyme critical for maintaining glutamate homeostasis at the tripartite synapse. Our previous studies indicate that the hippocampus may be particularly vulnerable to GDH deficiency in central nervous system (CNS). Here, we first asked whether mice with a homozygous deletion of Glud1 in CNS (CNS‐Glud1 ?/? mice) express different levels of glutamate in hippocampus, and found elevated glutamate as well as glutamine in dorsal and ventral hippocampus, and increased glutamine in medial prefrontal cortex (mPFC). l ‐serine and d ‐serine, which contribute to glutamate homeostasis and NMDA receptor function, are increased in ventral but not dorsal hippocampus, and in mPFC. Protein expression levels of the GABA synthesis enzyme glutamate decarboxylase (GAD) GAD67 were decreased in the ventral hippocampus as well. Behavioral analysis revealed deficits in visual, spatial and social novelty recognition abilities, which require intact hippocampal‐prefrontal cortex circuitry. Finally, hippocampus‐dependent contextual fear retrieval was deficient in CNS‐Glud1 ?/? mice, and c‐Fos expression (indicative of neuronal activation) in the CA1 pyramidal layer was reduced immediately following this task. These data point to hippocampal subregion‐dependent disruption in glutamate homeostasis and excitatory/inhibitory balance, and to behavioral deficits that support a decline in hippocampal‐prefrontal cortex connectivity. Together with our previous data, these findings also point to different patterns of basal and activity‐induced hippocampal abnormalities in these mice. In sum, GDH contributes to healthy hippocampal and PFC function; disturbed GDH function is relevant to several psychiatric and neurological disorders.     

Selective prefrontal cortex responses to joint attention in early infancy

The process by which two people share attention towards the same object or event is called joint attention. Joint attention and the underlying triadic representations between self, other person and object are thought to be unique to humans, supporting teaching, cooperation and language learning. Despite the progress that has been made in understanding the behavioural importance of joint attention during early social development, almost nothing is known about the brain substrate that supports joint attention in the developing infant. We examined responses in five-month-old infants'' prefrontal cortex during triadic social interactions using near-infrared spectroscopy. The results demonstrate that, even by the age of five months, infants are sensitive to triadic interactions and, like adults, they recruit a specific brain region localized in left dorsal prefrontal cortex when engaged in joint attention with another person. This suggests that the human infant is neurobiologically prepared for sharing attention with other humans, which may provide the basis for a wide variety of uniquely human social and cultural learning processes.     

Oscillations in the prefrontal cortex: a gateway to memory and attention

We consider the potential role of oscillations in the prefrontal cortex (PFC) in mediating attention, working memory and memory consolidation. Activity in the theta, beta, and gamma bands is related to communication between PFC and different brain areas. While gamma/beta oscillations mediate bottom-up and top-down interactions between PFC and visual cortices, related to attention, theta rhythms are engaged by hippocampal/PFC interplay. These interactions are dynamic, depending on the nature and relevance of the information currently being processed. The profound modifications of the PFC neuronal network associated with changes in oscillatory coherence are controlled by neuromodulators such as dopamine, which thereby allow or prevent the formation of cell assemblies for information encoding and storage.     

Traveling waves in the prefrontal cortex during working memory

Neural oscillations are evident across cortex but their spatial structure is not well- explored. Are oscillations stationary or do they form “traveling waves”, i.e., spatially organized patterns whose peaks and troughs move sequentially across cortex? Here, we show that oscillations in the prefrontal cortex (PFC) organized as traveling waves in the theta (4-8Hz), alpha (8-12Hz) and beta (12-30Hz) bands. Some traveling waves were planar but most rotated. The waves were modulated during performance of a working memory task. During baseline conditions, waves flowed bidirectionally along a specific axis of orientation. Waves in different frequency bands could travel in different directions. During task performance, there was an increase in waves in one direction over the other, especially in the beta band.     

Forebrain NR2B overexpression facilitating the prefrontal cortex long-term potentiation and enhancing working memory function in mice

Prefrontal cortex plays an important role in working memory, attention regulation and behavioral inhibition. Its functions are associated with NMDA receptors. However, there is little information regarding the roles of NMDA receptor NR2B subunit in prefrontal cortical synaptic plasticity and prefrontal cortex-related working memory. Whether the up-regulation of NR2B subunit influences prefrontal cortical synaptic plasticity and working memory is not yet clear. In the present study, we measured prefrontal cortical synaptic plasticity and working memory function in NR2B overexpressing transgenic mice. In vitro electrophysiological data showed that overexpression of NR2B specifically in the forebrain region resulted in enhancement of prefrontal cortical long-term potentiation (LTP) but did not alter long-term depression (LTD). The enhanced LTP was completely abolished by a NR2B subunit selective antagonist, Ro25-6981, indicating that overexpression of NR2B subunit is responsible for enhanced LTP. In addition, NR2B transgenic mice exhibited better performance in a set of working memory paradigms including delay no-match-to-place T-maze, working memory version of water maze and odor span task. Our study provides evidence that NR2B subunit of NMDA receptor in prefrontal cortex is critical for prefrontal cortex LTP and prefrontal cortex-related working memory.     

Dynamics of population code for working memory in the prefrontal cortex

Some neurons (delay cells) in the prefrontal cortex elevate their activities throughout the time period during which the animal is required to remember past events and prepare future behavior, suggesting that working memory is mediated by continuous neural activity. It is unknown, however, how working memory is represented within a population of prefrontal cortical neurons. We recorded from neuronal ensembles in the prefrontal cortex as rats learned a new delayed alternation task. Ensemble activities changed in parallel with behavioral learning so that they increasingly allowed correct decoding of previous and future goal choices. In well-trained rats, considerable decoding was possible based on only a few neurons and after removing continuously active delay cells. These results show that neural activity in the prefrontal cortex changes dynamically during new task learning so that working memory is robustly represented and that working memory can be mediated by sequential activation of different neural populations.     

A comparative review of rodent prefrontal cortex and working memory

The prefrontal cortex is critical to working memory processes. Current theories of prefrontal function are largely based on primate behavioural and electrophysiological data. As molecular genetic techniques advance in mice, so investigations into the rodent prefrontal cortex should expand, such that rodent models of prefrontal function during working memory may be used to study the synaptic and molecular basis of the phenomenon. This review attempts to summarize aspects of published data that pertain to working memory and suggest directions that will allow a coherent comparison of prefrontal function and interaction in monkey, rat and mouse.     

Neuronal discharges and gamma oscillations explicitly reflect visual consciousness in the lateral prefrontal cortex

Neuronal discharges in the primate temporal lobe, but not in the striate and extrastriate cortex, reliably reflect stimulus awareness. However, it is not clear whether visual consciousness should be uniquely localized in the temporal association cortex. Here we used binocular flash suppression to investigate whether visual awareness is also explicitly reflected in feature-selective neural activity of the macaque lateral prefrontal cortex (LPFC), a cortical area reciprocally connected to the temporal lobe. We show that neuronal discharges in the majority of single units and recording sites in the LPFC follow the phenomenal perception of a preferred stimulus. Furthermore, visual awareness is reliably reflected in the power modulation of high-frequency (>50?Hz) local field potentials in sites where spiking activity is found to be perceptually modulated. Our results suggest that the activity of neuronal populations in at least two association cortical areas represents the content of conscious visual perception.     

Neuronal responses in an isolated slab of the cat auditory cortex to intracortical stimulation

Neuronal responses in an isolated slab (area AI) to intracortical pulsed electrical stimulation at the level of layer IV were investigated extracellularly in acute experiments on cats immobilized with D-tubocurarine. Responding neurons were found in all layers of the slab. The character of their distribution by depth in the slab depended on the distance between recording and stimulating electrodes. The latent period of responses of different neurons ranged from 0.8 to 25 msec. With interelectrode distances of 0.5–2 mm most neurons responded mono- and disynaptically. However, responses of many neurons had a latent period of over 4 msec, i.e., they were polysynaptic. This indicates the complex character of interneuronal interactions, even in a limited area of the cortex. After intracortical stimulation no after-discharges with a latent period of over 40 msec could be recorded in the isolated slab of auditory cortex.I. I. Mechnikov Odessa State University. Translated from Neirofiziologiya, Vol. 14, No. 1, pp. 85–93, January–February, 1982.     

Neuronal activity in the prefrontal cortex in rats with various typological features during emotional affect

Unit activity in the right and left prefrontal cortex was recorded in male Wistar rats after testing by the emotional resonance technique. Rats were divided in two groups by their reaction to the suffering cry of a partner. Rats from the group A ("altruists") escaped partner's crying, and those from the group E ("egoists") did not. Activity of neurons was analyzed in hungry rats, after feeding, during intracranial emotionally positive and negative stimulation, and during crying of the rat partner. Some differences in neural activity between A and E groups were revealed. In the hungry state the rate of neuronal discharges was higher in the A group. In both groups of animals the positive emotional stimulation was accompanied by more intensive neuronal reaction that the negative stimulation, but in the E group increase in the rate of neuronal discharges in both hemispheres was significantly more pronounced. Negative stimulation produced in both groups a significantly greater activation in the left hemisphere than in the right one while during the positive stimulation the neural activity was more intensive in the left hemisphere. The neuronal reaction to partner's crying was significantly higher in the A group in both hemispheres, while the neuronal activity in E group did not significantly change.     

Neuronal responses of an isolated slab of cat auditory cortex to intracortical stimulation

Neuronal responses of an isolated slab of auditory cortex (area AI) to intracortical stimulation at the level IV were studied in curarized cats by extracellular recording 3 weeks after isolation. Dispersion of response latencies in the isolated slab was reduced (compared with that observed soon after isolation); the predominant responses were mono- and disynaptic, and the number of discharges consisting of bursts of spikes increased. However, despite simplification of the structural and functional organization of the chronically isolated slab of auditory cortex, the conditions for complex polysynaptic interaction between neurons of all layers were preserved in it, and in each layer the character of such interaction depended on the distance of the neuron from the focus of origin of the excitation. [In the chronically isolated slab of auditory cortex, just as in the acutely isolated slab, late reponses of over 40 msec were absent.]I. I. Mechnikov Odessa State University. Translated from Neirofiziologiya, Vol. 14, No. 5, pp. 462–469, September–October, 1982.     

The prefrontal cortex and working memory: physiology and brain imaging

Sustained activity has been recorded in the prefrontal cortex during working memory tasks. First, we compare the anatomical distribution of this activity in humans and monkeys. Then, we show that it reflects many factors, maintenance of the items presented, preparation for the response, transformation of the items during the delay, task rules and task goals. Finally, we point out that sustained activity has also been recorded in other areas, such as the parietal cortex. We suggest that the key to prefrontal cortex lies not in the maintenance of sensory information but in the prospective use of that information for behaviour.     

Expression of long-term depression underlies visual recognition memory

The modifications occurring in the brain during learning and memory are still poorly understood but may involve long-lasting changes in synaptic transmission (synaptic plasticity). In perirhinal cortex, a lasting decrement in neuronal responsiveness is associated with visual familiarity discrimination, leading to the hypothesis that long-term depression (LTD)-like synaptic plasticity may underlie recognition memory. LTD relies on internalization of AMPA receptors (AMPARs) through interaction between their GluR2 subunits and AP2, the clathrin adaptor protein required for endocytosis. We demonstrate that a peptide that blocks interactions between GluR2 and AP2 blocks LTD in perirhinal cortex in vitro. Viral transduction of this peptide in perirhinal cortex produced striking deficits in visual recognition memory. Furthermore, there was a deficit of LTD in perirhinal cortex slices from virally transduced, recognition memory-deficient animals. These results suggest that internalization of AMPA receptors, a process critical for the expression of LTD in perirhinal cortex, underlies visual recognition memory.     

Neuronal inhibitory responses to intracortical stimulation of an isolated slab of cat auditory cortex

Neuronal responses of an isolated slab of cortex to intracortical stimulation were studied intracellularly. The predominant responses were primary IPSPs. Their latent periods did not exceed 10 msec. Within the volume of cortex studied, neurons inhibited in response to stimulation were most numerous in the upper layers (II, III). Predominance of disynaptic IPSPs is evidence of the important role of cortical interneurons in their genesis. It is concluded from the results that primary IPSPs limit the spread of excitation primarily in the activated area of cortex. Since involvement of neurons of the isolated slab in the inhibition process takes place for only 10 msec after stimulation, neurons giving spike responses to intracortical stimulation with a longer latent period can transmit information into other brain zones. The role of duration of IPSP in the dynamics of interneuronal interaction in the cerebral cortex is discussed.I. I. Mechnikov Odessa State University. Translated from Neirofiziologiya, Vol. 16, No. 1. pp. 42–49, January–February, 1984.     

Prediction error signaling explains neuronal mismatch responses in the medial prefrontal cortex

The mismatch negativity (MMN) is a key biomarker of automatic deviance detection thought to emerge from 2 cortical sources. First, the auditory cortex (AC) encodes spectral regularities and reports frequency-specific deviances. Then, more abstract representations in the prefrontal cortex (PFC) allow to detect contextual changes of potential behavioral relevance. However, the precise location and time asynchronies between neuronal correlates underlying this frontotemporal network remain unclear and elusive. Our study presented auditory oddball paradigms along with “no-repetition” controls to record mismatch responses in neuronal spiking activity and local field potentials at the rat medial PFC. Whereas mismatch responses in the auditory system are mainly induced by stimulus-dependent effects, we found that auditory responsiveness in the PFC was driven by unpredictability, yielding context-dependent, comparatively delayed, more robust and longer-lasting mismatch responses mostly comprised of prediction error signaling activity. This characteristically different composition discarded that mismatch responses in the PFC could be simply inherited or amplified downstream from the auditory system. Conversely, it is more plausible for the PFC to exert top-down influences on the AC, since the PFC exhibited flexible and potent predictive processing, capable of suppressing redundant input more efficiently than the AC. Remarkably, the time course of the mismatch responses we observed in the spiking activity and local field potentials of the AC and the PFC combined coincided with the time course of the large-scale MMN-like signals reported in the rat brain, thereby linking the microscopic, mesoscopic, and macroscopic levels of automatic deviance detection.

Neuronal recordings in the medial prefrontal cortex of the rat demonstrate that auditory mismatch responses are purely composed of prediction error signaling activity, independent from the spectral effects that drive the auditory system.     

Neuronal responses in the limbic cortex of awake cats during defensive conditioning

Spike activity was investigated in limbic cortex neurons during defensive conditioning to acoustic stimulation in chronic experiments on cats. A relationship was found between the numbers of neurons responding, their contribution to formation of a temporal connection, and the duration of the acoustic stimulus. Phasic responses of 50–500 msec duration with latencies of 15–50 msec were observed for the most part. Intensive spike response with a minimum latency of 15 msec and a duration of between 200 msec and 2.5 sec evolved in most cells (95.1% in field 24 and 83% in field 32) in response to electrical stimulation. Response to acoustic stimulation rose during defensive conditioning in 33.3% cells and declined and finally disappeared in 13.3%, but response at the site where reinforcement was abolished was reproduced in all these cells. It was thus found that the numbers of limbic cortex neurons responding to sound not only fails to increase but actually decreases after training. The limbic cortex is thought to play its most active part in conditioning response to a recognized signal during the period preceding the awaited painful reinforcement.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 5, pp. 660–669, September–October, 1986.