Long-term potentiation of thalamocortical transmission in the adult visual cortex in vivo.

It has been suggested that NMDA receptor-dependent synaptic strengthening, like that observed after long-term potentiation (LTP), is a mechanism by which experience modifies responses in the neocortex. We report here that patterned (theta burst) stimulation of the dorsal lateral geniculate nucleus reliably induces LTP of field potentials (FPs) evoked in primary visual cortex (Oc1) of adult rats in vivo. The response enhancement is saturable, long-lasting, and dependent on NMDA receptor activation. To determine the laminar locus of these changes, current source density (CSD) analysis was performed on FP profiles obtained before and after LTP induction. LTP was accompanied by an enhancement of synaptic current sinks located in thalamorecipient (layer IV and deep layer III) and supragranular (layers II/III) cell layers. We also examined immunocytochemical labeling for the immediate early gene zif-268 1 hr after induction of LTP. In concert with the laminar changes observed in CSD analyses, we observed a significant increase in the number of zif-268-immunopositive neurons in layers II-IV that occurred over a wide extent of Oc1. Last, we investigated the functional consequences of LTP induction by monitoring changes in visually evoked potentials. After LTP, we observed that the cortical response to a full-field flash was significantly enhanced and that responses to grating stimuli were increased across a range of spatial frequencies. These findings are consistent with growing evidence that primary sensory cortex remains plastic into adulthood, and they show that the mechanisms of LTP can contribute to this plasticity.

Developmental inhibitory gate controls the relay of activity to the superficial layers of the visual cortex.

A developmental reduction in the radial transmission of synaptic activity has been proposed to underlie the end of the critical period for experience-dependent modification in layers II/III of the visual cortex. Using paired-pulse stimulation, we investigated in visual cortical slices how the propagation of synaptic activity to the superficial layers changes during development and how this process is affected by sensory experience. The results can be summarized as follows. (1) Layers II/III responses to repetitive stimulation of the white matter become increasingly depressed between the third and sixth week of postnatal development, a time course that parallels the end of the critical period. (2) Paired-pulse depression is reduced after dark rearing and also by blocking inhibitory synaptic transmission. (3) Paired-pulse depression and its regulation by age and sensory experience is more pronounced when stimulation is applied to the white matter than when applied to layer IV. Together, these results are consistent with the idea that the maturation of intracortical inhibition reduces the capability of the cortex to relay incoming high-frequency patterns of activity to the supragranular layers.

Bidirectional, activity-dependent regulation of glutamate receptors in the adult hippocampus in vivo.

Experience-dependent regulation of synaptic strength has been suggested as a physiological mechanism by which memory storage occurs in the brain. Although modifications in postsynaptic glutamate receptor levels have long been hypothesized to be a molecular basis for long-lasting regulation of synaptic strength, direct evidence obtained in the intact brain has been lacking. Here we show that in the adult brain in vivo, synaptic glutamate receptor trafficking is bidirectionally, and reversibly, modified by NMDA receptor-dependent synaptic plasticity and that changes in glutamate receptor protein levels accurately predict changes in synaptic strength. These findings support the idea that memories can be encoded by the precise experience-dependent assignment of glutamate receptors to synapses in the brain.

Bidirectional modification of CA1 synapses in the adult hippocampus in vivo.

Memories are believed to be stored by synaptic modifications. One type of activity-dependent synaptic modification, long-term potentiation (LTP), has received considerable attention as a possible memory mechanism, particularly in hippocampus. However, use-dependent decreases in synaptic strength can store information as well. A form of homosynaptic long-term depression (LTD) has been described and widely studied in the CA1 region of the developing hippocampus in vitro. However, the relevance of this model of LTD to memory has been questioned because of failures to replicate it in the adult brain in vitro and, more recently, in vivo. Here we re-examine this important issue and find that homosynaptic LTD can in fact be elicited in the adult hippocampus in vivo, that it has all the properties described in immature CA1 in vitro, and that LTD and LTP are reversible modifications of the same Schaffer collateral synapses. Thus homosynaptic LTD is not peculiar to brain slices, nor is it only of developmental significance. Rather, out data suggest that the mechanisms of LTD and LTD may be equal partners in the mneumonic operations of hippocampal neural networks.

Effects of perforant path procaine on hippocampal type 2 rhythmical slow-wave activity (theta) in the urethane-anesthetized rat.

Previous research has suggested that the entorhinal cortex plays a major role in the production of type 1 rhythmical slow-wave activity (RSA) recorded in the hippocampus of the freely moving preparation. In the present experiment we investigated the contribution of the entorhinal cortex to the type 2 fields recorded under urethane anesthesia. Rats had stimulating electrodes and cannulae filled with procaine positioned in the perforant pathway of one or both hemispheres. Recording electrodes were positioned in the dorsal hippocampus of each hemisphere to record perforant path and commissural/associational evoked potentials and RSA fields. Following unilateral procaine blockade, a decrease in RSA amplitude was observed in the stratum oriens and fissure regions of both hemispheres. Concomitant with this change in RSA, there was a loss of perforant path evoked responses, although commissural/associational control potentials remained unaltered. A greater reduction in RSA amplitude was observed following bilateral procaine microinfusion. RSA phase reversal also occurred more dorsally in microelectrode depth profiles conducted through the hippocampus during perforant path inactivation. In current source density analyses performed under baseline conditions, large rhythmic sinks were observed in stratum oriens, in stratum radiatum, and in strata adjacent to the hippocampal fissure. A rhythmic source was often observed in stratum pyramidale. Following perforant path inactivation decreases in the magnitude of the phasic sinks located near the fissure and stratum radiatum were observed. In contrast to the reduction in RSA amplitude observed in the stratum oriens region, the sink in this region and the source in stratum pyramidale remained relatively unaltered. These results demonstrate that the entorhinal region contributes to the production of RSA observed under urethane anesthesia. Furthermore, the CSD and amplitude changes following perforant path inactivation suggest that a substantial portion of RSA recorded in stratum oriens may result from ventrally located RSA dipoles.

Effects of kainic acid microinfusions on hippocampal type 2 RSA (theta).

This study investigated the effects of bilateral, selective lesions of subfield CA3, produced by intrahippocampal administration of kainic acid, on the generation of hippocampal type 2 RSA. Within 4 weeks of lesioning, animals were anesthetized with urethane and microelectrode depth profiles were performed throughout the dorsal-ventral extent of the hippocampus. In control animals, spontaneous and stimulation-induced RSA was present at the amplitude maxima in stratum oriens of the CA1 and at the level of the hippocampal fissure. Animals that received intrahippocampal microinfusions of kainic acid showed a significant reduction of RSA amplitude at both the stratum oriens and fissure regions. These results suggest that the CA3 subfield may play an important role in the production of type 2 RSA.

Stimulation-induced RSA-like field activity in region CA1 of the hippocampal slice: amplitude maxima and topography.

In the present experiment RSA-patterned stimulation was applied to afferents in the CA1 region of the hippocampal slice preparation and depth profiles of the resultant field activity were performed. RSA-patterned stimulation applied to the stratum lacunosum-moleculare region resulted in field activity through the CA1 region with similar morphology, phase, and amplitude profiles to the type 1 RSA profile found in vivo. In contrast, RSA-patterned stimulation applied to the stratum oriens and midstratum radiatum regions did not result in field profiles characteristic of the RSA recorded in vivo. The results of the present study confirm predictions made by previous modelling experiments and CSD analyses performed in the freely moving animal, which suggest that the type 1 RSA profile is primarily the result of distal excitation onto CA1 pyramidal cells.

Induction of RSA-like oscillations in both the in-vitro and in-vivo hippocampus.

Although the medial septum is generally regarded as the 'pacemaker' of hippocampal Rhythmical Slow Activity (RSA) its precise role has recently been queried, as RSA-like activity can be recorded from in-vitro juvenile hippocampal slices. Here we demonstrate that a critical condition for in-vitro RSA generation in the adult slice is concurrent excitation (provided by bath application of either carbachol or glutamate) and disinhibition (bath application of picrotoxin). Furthermore, under similar conditions of excitation and disinhibition, the in-vivo adult hippocampus is also capable of generating RSA-like oscillations in the absence of septal influences. These findings suggest that, in-vivo, the medial septum may modulate an intrinsically generated hippocampal oscillation through its excitatory and disinhibitory efferents.

Alpha 2-noradrenergic modulation of hippocampal theta activity.

The purpose of the present study was to determine the role of norepinephrine in the generation of hippocampal theta activity. Experiments were performed on urethane-anesthetized rats, implanted with recording electrodes in the dentate gyrus and stimulating electrodes in the dorso-medial posterior hypothalamus. The effects of norepinephrine on hippocampal theta activity was studied by directly infusing norepinephrine and other noradrenergic agents into the hippocampus. Norepinephrine microinfusion produced a decrease in the amplitude of theta activity as observed in the polygraph chart record. Subsequent spectral analyses demonstrated a decrease in power at peak theta frequencies, as well as a decrease in power at frequencies between 20-25 Hz (noise). The inhibitory effect of norepinephrine on hippocampal type 2 theta activity was found to be mediated by alpha 2-adrenergic receptors. Microinfusions of an alpha 2 agonist (detomidine) mimicked the effects produced by norepinephrine, whereas alpha 1 and beta agonists were ineffective. The inhibitory effect of detomidine was blocked by microinfusions of an alpha 2 antagonist (tolazoline), which indicates that the site of action was specific to the noradrenergic alpha 2 receptor.

Modality specific type 2 theta production in the immobile rat.

The purpose of the present study was to compare the relative effectiveness of stimulation of different sensory modalities in eliciting Type 2 theta in the rat in the presence or absence of a ferret. Visual, auditory, and tactile stimuli were presented to rats in both conditions. Tactile stimulation produced more movement than either visual or auditory stimuli when the ferret was present. In both conditions, however, more Type 2 theta was observed in response to tactile or visual stimulation than to auditory stimulation. In the arousal condition, stimulation of tactile and auditory modalities resulted in significant increases in the amount of Type 2 theta produced. Input to the visual modality produced high levels of Type 2 theta production in both low- and high-arousal conditions. It is argued that Type 2 theta is not necessarily a precursor to movement but rather sensory processing while in a high state of arousal.