A test of the reverberatory activity hypothesis for hippocampal 'place' cells.

One of several tenable hypotheses that can be proposed to explain the complex dynamics of spatially selective hippocampal neural activity postulates that the region of space over which a given cell receives its external input is actually much smaller than the classical 'place field.' According to this notion, the later portions of the field reflect some form of network hysteresis resulting from 'reverberatory' activity within reentrant, synaptically coupled cell assemblies within the hippocampus. This hypothesis predicts that transient, global inhibition, induced after the onset of firing, might truncate the remainder of the place field. To test this hypothesis, principal afferents to the hippocampus were stimulated bilaterally in rats running on a circular track, evoking widespread inhibition throughout the hippocampus, and abolishing all spike activity from simultaneously recorded populations of CA1 pyramidal cells for periods of 150-300 ms. Stimulation at any point within the place field of a given cell suppressed firing only for such brief intervals, followed by an immediate resumption for the remainder of the field. These results suggest that without additional cellular and/or synaptic mechanisms, reverberatory activity alone within the hippocampus does not account for the shape and spatial extent of place fields.

Effects of aerosol-vapor JP-8 jet fuel on the functional observational battery, and learning and memory in the rat.

To determine whether JP-8 jet fuel affects parameters of the Functional Observational Battery (FOB), visual discrimination, or spatial learning and memory, the authors exposed groups of male Fischer Brown Norway hybrid rats for 28 d to aerosol/vapor-delivered JP-8, or to JP-8 followed by 15 min of aerosolized substance P analogue, or to sham-confined fresh room air. Behavioral testing was accomplished with the U.S. Environmental Protection Agency's Functional Observational Battery. The authors used the Morris swim task to test visual and spatial learning and memory testing. The spatial test included examination of memory for the original target location following 15 d of JP-8 exposure, as well as a 3-d new target location learning paradigm implemented the day that followed the final day of exposure. Only JP-8 exposed animals had significant weight loss by the 2nd week of exposure compared with JP-8 with substance P and control rats; this finding compares with those of prior studies of JP-8 jet fuel. Rats exposed to JP-8 with or without substance P exhibited significantly greater rearing and less grooming behavior over time than did controls during Functional Observational Battery open-field testing. Exposed rats also swam significantly faster than controls during the new target location training and testing, thus supporting the increased activity noted during Functional Observational Battery testing. There were no significant differences between the exposed and control groups' performances during acquisition, retention, or learning of the new platform location in either the visual discrimination or spatial version of the Morris swim task. The data suggest that although visual discrimination and spatial learning and memory were not disrupted by JP-8 exposure, arousal indices and activity measures were distinctly different in these animals.

Hippocampal synaptic plasticity is modulated by theta rhythm in the fascia dentata of adult and aged freely behaving rats.

A modulatory role for the hippocampal theta rhythm in synaptic plasticity is suggested by the observations that theta occurs during exploratory behaviors, spatial learning is impaired when the theta rhythm is disrupted, and excitation of hippocampal principal cells is phase-coupled to the theta wave. The theta phase affects the nature of the plasticity induced in urethane-anesthetized rats and in the carbachol-treated in vitro slice preparation, but these oscillations are phenomenologically different from natural theta, and the effects of theta phase on plasticity under natural conditions have not been reported. We therefore examined the effects of theta phase on the magnitude of long-term potentiation (LTP) in awake rats running on a linear track for a food reward. Twelve adult and 10 aged F344 male rats were implanted with a stimulating electrode in the perforant path and a recording electrode in the hilus of the fascia dentata. Stimuli were delivered at the peak or trough of the hilar theta rhythm. In both adult and aged, memory-impaired rats, LTP lasting at least 48 h was induced when stimuli were delivered at the positive theta peak, whereas LTP was not induced when stimuli were delivered at the negative troughs. Consistent with the finding that the threshold for LTP induction is increased at this synapse in old rats, the magnitude of LTP induced at the peak of theta rhythm was significantly lower in old animals. These data confirm that LTP can be modulated by locomotion-induced theta, and that this modulation is at least qualitatively preserved across age.

Regulation of T cell activation, anxiety, and male aggression by RGS2.

Regulators of G protein signaling (RGS) proteins accelerate the GTPase activity of Galpha protein subunits in vitro, negatively regulating G protein-coupled receptor signaling. The physiological role of mammalian RGS proteins is largely unknown. The RGS family member rgs2 was cloned as an immediate early response gene up-regulated in T lymphocytes after activation. To investigate the role of RGS2 in vivo, we generated rgs2-deficient mice. We show that targeted mutation of rgs2 in mice leads to reduced T cell proliferation and IL-2 production, which translates in an impaired antiviral immunity in vivo. Interestingly, rgs2(-/-) mice also display increased anxiety responses and decreased male aggression in the absence of cognitive or motor deficits. RGS2 also controls synaptic development and basal electrical activity in hippocampal CA1 neurons. Thus, RGS2 plays an important role in T cell activation, synapse development in the hippocampus, and emotive behaviors.

LTP induction threshold change in old rats at the perforant path--granule cell synapse.

Old, memory-deficient rats do not show a change in the threshold for long-term potentiation (LTP) induction in hippocampal region CA1. This observation suggests that defective NMDA receptor mechanisms at the Schaffer collateral-CA 1 pyramidal cell synapse cannot explain age-related LTP induction deficits that are observed under some stimulation protocols. The effects of aging on functional electrophysiology are not, however, identical between hippocampal subregions. In fact, at the perforant path-granule cell synapse of rats NMDA receptor-mediated responses are reduced, suggesting a possible change in the threshold for LTP induction at this synapse. This hypothesis was tested in the present experiment. We found that when weak orthodromic stimulation of medial perforant path fibers is paired with intracellular current injection of granule cells, the threshold for LTP induction is elevated in aged, spatial memory-impaired rats compared to middle-aged and young controls. Thus, in addition to there being fewer total medial perforant path synaptic contacts in old rats, greater depolarization and input convergence is required before durable modification of synaptic strength can be induced.

Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory.

It is widely believed that the brain processes information and stores memories by modifying and stabilizing synaptic connections between neurons. In experimental models of synaptic plasticity, such as long-term potentiation (LTP), the stabilization of changes in synaptic strength requires rapid de novo RNA and protein synthesis. Candidate genes, which could underlie activity-dependent plasticity, have been identified on the basis of their rapid induction in brain neurons. Immediate-early genes (IEGs) are induced in hippocampal neurons by high-frequency electrical stimulation that induces LTP and by behavioral training that results in long-term memory (LTM) formation. Here, we investigated the role of the IEG Arc (also termed Arg3.1) in hippocampal plasticity. Arc protein is known to be enriched in dendrites of hippocampal neurons where it associates with cytoskeletal proteins (Lyford et al., 1995). Arc is also notable in that its mRNA and protein accumulate in dendrites at sites of recent synaptic activity (Steward et al., 1998). We used intrahippocampal infusions of antisense oligodeoxynucleotides to inhibit Arc protein expression and examined the effect of this treatment on both LTP and spatial learning. Our studies show that disruption of Arc protein expression impairs the maintenance phase of LTP without affecting its induction and impairs consolidation of LTM for spatial water task training without affecting task acquisition or short-term memory. Thus, Arc appears to play a fundamental role in the stabilization of activity-dependent hippocampal plasticity.

Effects of age on the generalization and incubation of memory in the F344 rat.

Freezing (immobility) in the presence of aversive stimuli is a species-specific behavior that is used as an operational measure of fear. Conditioning of this response to discrete sensory stimuli and environmental context cues has been used as a tool to study the neuropsychology of memory dynamics and their development over the lifespan. Three age groups of F344 rats (3, 9, and 27 month) received tone-foot shock pairing (or tone only) in a distinctive chamber on two consecutive days. Separate subgroups of rats from each age group were then tested, at retention intervals of 1, 20, 40, or 60 days, for context-mediated fear in the environment in which they were trained, for generalization of the fear response to a novel chamber, and for fear of the tone. Beginning at day 20, the 27-month-old rats exhibited less freezing behavior than did younger rats when tested in the conditioning context. This age difference was a result of freezing behavior becoming progressively stronger with time in the two younger age groups, a phenomenon that has been referred to as memory incubation. Incubation of the contextual fear response was not detected in the old rats. In a novel context, all age groups exhibited significantly more freezing than did control animals. There was also pronounced incubation of this generalized freezing response, and the extent of incubation declined significantly with age. In the novel context, the freezing response to the tone was robust in all age groups and increased over time, in constant proportion to the degree of freezing elicited by the novel context itself, prior to tone onset. The fact that old animals are known to be relatively selectively impaired in forms of memory that depend on a functional hippocampus suggests a possible explanation for the reduced incubation effects seen in old rats; however, whether the increased expression of fear over time is mediated by a hippocampal-dependent memory consolidation process or whether it reflects a generalized increase in the gain of the circuitry mediating the fear response itself, remains to be determined.