Reliable induction of sleep spindles with intracranial electrical pulse stimulation.

Neocortical sleep spindles have been shown to occur more frequently following a memory task, suggesting that a method to increase spindle activity could improve memory processing. Stimulation of the neocortex can elicit a slow oscillation (SO) and a spindle, but the feasibility of this method to boost SO and spindles over time has not been tested. In rats with implanted neocortical electrodes, stimulation during slow wave sleep significantly increased SO and spindle rates compared to control rest periods before and after the stimulation session. Coordination between hippocampal sharp-wave ripples and spindles also increased. These effects were reproducible across five consecutive days of testing, demonstrating the viability of this method to increase SO and spindles.

Exposure to complex environments results in more sparse representations of space in the hippocampus.

The neural circuitry mediating sensory and motor representations is adaptively tuned by an animal's interaction with its environment. Similarly, higher order representations such as spatial memories can be modified by exposure to a complex environment (CE), but in this case the changes in brain circuitry that mediate the effect are less well understood. Here, we show that prolonged CE exposure was associated with increased selectivity of CA1 "place cells" to a particular recording arena compared to a social control (SC) group. Furthermore, fewer CA1 and DG neurons in the CE group expressed high levels of Arc protein, a marker of recent activation, following brief exposure to a completely novel environment. The reduced Arc expression was not attributable to overall changes in cell density or number. These data indicate that one effect of CE exposure is to modify high-level spatial representations in the brain by increasing the sparsity of population coding within networks of neurons. Greater sparsity could result in a more efficient and compact coding system that might alter behavioural performance on spatial tasks. The results from a behavioural experiment were consistent with this hypothesis, as CE-treated animals habituated more rapidly to a novel environment despite showing equivalent initial responding.

Enhanced hippocampal neuronal excitability and LTP persistence associated with reduced behavioral flexibility in the maternal immune activation model of schizophrenia.

Individuals with schizophrenia display a number of structural and cytoarchitectural alterations in the hippocampus, suggesting that other functions such as synaptic plasticity may also be modified. Altered hippocampal plasticity is likely to affect memory processing, and therefore any such pathology may contribute to the cognitive symptoms of schizophrenia, which includes prominent memory impairment. The current study tested whether prenatal exposure to infection, an environmental risk factor that has previously been associated with schizophrenia produced changes in hippocampal synaptic transmission or plasticity, using the maternal immune activation (MIA) animal model. We also assessed performance in hippocampus-dependent memory tasks to determine whether altered plasticity is associated with memory dysfunction. MIA did not alter basal synaptic transmission in either the dentate gyrus or CA1 of freely moving adult rats. It did, however, result in increased paired-pulse facilitation of the dentate gyrus population spike and an enhanced persistence of dentate long-term potentiation. MIA animals displayed slower learning of a reversed platform location in the water maze, and a similarly slowed learning during reversal in a spatial plus maze task. Together these findings are indicative of reduced behavioral flexibility in response to changes in task requirements. The results are consistent with the hypothesis that hippocampal plasticity is altered in schizophrenia, and that this change in plasticity mechanisms may underlie some aspects of cognitive dysfunction in this disorder.

Physiological effects of enriched environment exposure and LTP induction in the hippocampus in vivo do not transfer faithfully to in vitro slices.

A number of experimental paradigms use in vitro brain slices to test for changes in synaptic transmission and plasticity following a behavioral manipulation. For example, a number of previous studies have reported a variety of effects of environmental enrichment (EE) exposure on field potential responses in hippocampal slices, but in no study was is it known what changes had been elicited in vivo. In the present study, we recorded from the hippocampus in vivo while rats underwent a brief period of EE. There was no detectable EE-induced change in synaptic efficacy in the dentate gyrus in vivo, but there was an increase in cellular excitability. In slices prepared from the same animals, we failed to observe any evidence of the excitability increase. We next tested whether LTP induction in vivo was better preserved in vitro. However, when slices from these rats were examined, there was no observable change in perforant path synaptic strength, although there was a modest increase in excitability that correlated with the increased excitability observed in vivo. These findings suggest that synaptic changes induced in vivo either are not preserved faithfully or are difficult to detect in hippocampal slices, while changes in cellular excitability are better preserved.

Altered plasticity in hippocampal CA1, but not dentate gyrus, following long-term environmental enrichment.

Exposure to an enriched environment can improve cognitive functioning in normal animals as well as in animal models of neurological disease and impairment. However, the physiological processes that mediate these changes are poorly understood. Previously we and others have found changes in hippocampal synaptic transmission and plasticity after 2-4 wk of enrichment although others have not observed effects. To determine whether long-term enrichment produces more robust changes, we housed rats continuously in an enriched environment for a minimum of 3 mo and then tested for effects on hippocampal physiology in vitro and in vivo. Enriched housing improved spatial learning compared with social and isolated housing, but surprisingly this was not accompanied by changes in basal synaptic transmission in either CA1 or the dentate gyrus as measured either in vitro or in vivo. This lack of change may reflect the operation of homeostatic mechanisms that keep global synaptic weights within a narrow range. In tests of synaptic plasticity, the induction of long-term potentiation was not changed in either CA1 or the dentate gyrus. However, in CA1 of enriched rats, there was less long-term depression in stratum radiatum, less depotentiation in stratum oriens, and altered paired-pulse inhibition of population spikes evoked in stratum oriens. These effects suggest that there are altered synaptic and network dynamics in hippocampal CA1 that contribute to the enrichment-related cognitive improvement.

Rapid visual stimulation induces N-methyl-D-aspartate receptor-dependent sensory long-term potentiation in the rat cortex.

Previously we have demonstrated that rapidly presented sensory stimulation (visual or auditory) can induce long-lasting increases in sensory evoked potentials recorded from the human cortex. Long-term potentiation was suggested as the underlying mechanism of these increases. In the present experiment, we applied the same visual paradigm to anesthetized rats to investigate the properties and mechanisms of this effect. Our results indicated that visual evoked responses were significantly enhanced for at least 1 h and, when followed, up to 5 h after the presentation of a 'photic tetanus.' Furthermore, the potentiation was N-methyl-D-aspartate receptor-dependent and cortically generated. This type of sensory long-term potentiation may underlie perceptual learning, and serves as a model system for investigating sensory-evoked plasticity.

Metabotropic glutamate receptors contribute to neocortical synaptic plasticity in vivo.

Metabotropic glutamate receptors (mGluRs) have been shown to be important for hippocampus-dependent memory, as well as activity-dependent synaptic plasticity in the hippocampus. In this study, we examined the role of mGluRs in the induction of two forms of activity-dependent synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), in the neocortex of awake, freely-moving rats. The mGluR antagonist AIDA was administered during the induction of LTP or LTD in the motor cortex. There was a 50% reduction of LTP induced in the early component of the evoked response, but there was no effect on the late component and no effect on the induction of LTD. Thus, mGluRs contribute to at least one form of activity dependent synaptic plasticity in the neocortex.

Effects of environmental enrichment exposure on synaptic transmission and plasticity in the hippocampus.

Exposure to an enriched environment (EE) is beneficial to the structure and function of the brain. The added sensory, social, and spatial complexity of the EE also improves cognitive functions such as memory in both healthy brains and damaged or diseased brains, yet the underlying neural mechanisms of these cognitive improvements are poorly understood. In particular, studies that have examined the effects of EE on cellular function in the hippocampus, a structure critical for memory storage, have produced somewhat confusing results. Experiments performed in ex vivo hippocampal slices have reported a variety of EE effects on synaptic transmission and plasticity in both CA1 and the dentate gyrus. However, together with data from in vivo recordings made during and after the EE treatment, the overall results suggest an evolution of changes in neuronal function in the hippocampus, whereby there is an early transient increase in cell activity and plasticity that gives rise to more subtle long-term enhancements in cellular and network function that may contribute to enhanced hippocampus-dependent cognition.