Place cell firing cannot support navigation without intact septal circuits.

Though it has been known for over half a century that interference with the normal activity of septohippocampal neurons can abolish hippocampal theta rhythmicity, a definitive answer to the question of its function has remained elusive. To clarify the role of septal circuits and theta in location-specific activity of place cells and spatial behavior, three drugs were delivered to the medial septum of rats: Tetracaine, a local anesthetic; muscimol, a GABA-A agonist; and gabazine, a GABA-A antagonist. All three drugs disrupted normal oscillatory activity in the hippocampus. However, tetracaine and muscimol both reduced spatial firing and interfered with the rat's ability to navigate to a hidden goal. After gabazine, location-specific firing was preserved in the absence of theta, but rats were unable to accurately locate the hidden goal. These results indicate that theta is unnecessary for location-specific firing of hippocampal cells, and that place cell activity cannot support accurate navigation when septal circuits are disrupted.

Short duration waveforms recorded extracellularly from freely moving rats are representative of axonal activity.

While extracellular somatic action potentials from freely moving rats have been well characterized, axonal activity has not. We report direct extracellular tetrode recordings of putative axons whose principal feature is a short duration waveform (SDW) with an average peak-trough length less than 179 µs. While SDW recordings using tetrodes have previously been treated as questionable or classified as cells, we hypothesize that they are representative of axonal activity. These waveforms have significantly shorter duration than somatic action potentials, are triphasic and are therefore similar to classic descriptions of microelectrode recordings in white matter and of in vitro action potential propagation along axons. We describe SDWs recorded from pure white-matter tracts including the alveus and corpus callosum. Recordings of several SDWs in the alveus exhibit grid-like firing patterns suggesting these axons carry spatial information from entorhinal cortical neurons. Finally, we locally injected the GABAA agonist Muscimol into layer CA1 of the hippocampus while simultaneously recording somatic activity and SDWs on the same tetrodes. The persistent activity of SDWs during Muscimol inactivation of somatic action potentials indicates that SDWs are representative of action potential propagation along axons projecting from more distal somata. This characterization is important as it illustrates the dangers of exclusively using spike duration as the sole determinant of unit type, particularly in the case of interneurons whose peak-trough times overlap with SDWs. It may also allow future studies to explore how axonal projections from disparate brain regions integrate spatial information in the hippocampus, and provide a basis for studying the effects of pharmaceutical agents on signal transmission in axons, and ultimately to aid in defining the potential role of axons in cognition.

Inhibition of protein kinase Mζ disrupts the stable spatial discharge of hippocampal place cells in a familiar environment.

It is widely held that spatial computations in the rodent hippocampus require the location-specific discharge of place cells that together form a stable cognitive map used to solve and perform spatial tasks. It is not known, however, if map stability requires persistent hippocampal synaptic strength changes that are vulnerable to blockade of protein kinase Mζ (PKMζ) phosphorylation activity, a manipulation that reverses hippocampal LTP and disrupts multiple forms of long-term memory. Here we report that acute intrahippocampal inhibition of PKMζ disrupts place cell activity in a familiar environment, where the map is expected to be stable. After this disruption, new, stable spatial firing patterns can later form, but the new and original maps are unrelated even though the rat is exposed to a constant environment. We therefore propose that the previously demonstrated erasure of stored spatial memory and the disruption of place cell firing are parallel effects of PKMζ blockade. We similarly propose that the known sparing of new spatial memory formation depends on the sparing of new map formation. On these bases, we argue that the loss of the map used to perform a practiced spatial task leads to behavioral performance deficits, and that synaptic plasticity maintained by PKMζ, which stabilizes the map, is essential for the proper expression of spatial memory.

Repetitive convulsant-induced seizures reduce the number but not precision of hippocampal place cells.

Repetitive one-per-day seizures induced in otherwise normal rats by the volatile convulsant flurothyl decrease the accuracy of locating a hidden goal without changing the mean location of goal selection. We now show that an 8-d series of such seizures degrades the spatial signal carried by the firing of hippocampal pyramidal cells and specifically reduces the information conveyed by the place cell subset of pyramidal cells. This degradation and a concomitant slowing of the hippocampal theta rhythm occur over time courses parallel to the development of the behavioral deficit and plausibly account for the impairment. The details of how pyramidal cell discharge weakens are, however, unexpected. Rather than a reduction in the precision of location-specific firing distributed evenly over all place cells, the number of place cells decreases with seizure number, although the remaining place cells remain quite intact. Thus, with serial seizures there is a cell-specific conversion of robust place cells to sporadically firing (<0.1 spike/s) "low-rate" cells as opposed to gradual loss of place cell resolution. This transformation occurs in the absence of significant changes in the discharge rate of hippocampal interneurons, suggesting that the decline in the number of place cells is not a simple matter of increased inhibitory tone. The cumulative transformation of place cells to low-rate cells by repetitive seizures may reflect a homeostatic, negative-feedback process.

The presence of a second rat has only subtle effects on the location-specific firing of hippocampal place cells.

We compared the spatial firing properties of hippocampal place cells as a hungry rat foraged for randomly scattered food pellets in a familiar environment while it was by itself and while it shared the arena with a second rat that also was trained in the same task. Our goal was to determine if the hippocampal mapping system remained functional in the presence of the second rat, despite a strong initial tendency of the two animals to stay close together and despite the increased complexity of the sensory surroundings. We found that almost all place cell firing fields were only marginally changed by introducing the second rat. In particular, there was no evidence of the remapping characteristic of place cells in a sufficiently different novel environment. Instead, firing fields became somewhat less well organized and slightly weaker in the presence of the second rat. These second order changes were found to be distance dependent; the degradation of firing properties was maximal when the two rats were near each other. We conclude that signals in the hippocampal mapping system are affected to a small enough extent that accurate navigational is still possible when the environment is enriched in this realistic fashion.

The effects on place cells of local scopolamine dialysis are mimicked by a mixture of two specific muscarinic antagonists.

Using a dialysis probe near CA1 hippocampal recording electrodes, we infused nonspecific (scopolamine) and specific (methoctramine, pirenzepine) antagonists of muscarinic cholinergic transmission to determine their effects on the positional firing properties of place cells. Both low (0.5 mM) and high (2.0 or 3.0 mM) scopolamine significantly decreased in-field firing rate, increased the ratio of out-of-field to in-field rate, and reduced the smoothness of rate maps, while tending to increase out-of-field rate. Thus, local nonspecific muscarinic blockade mimicked the effects seen with intracerebroventricular application, suggesting that blockade of receptors local to the recorded cells plays an essential role. Unexpectedly, dialysis of scopolamine reduced locomotor activity, again duplicating the effects of intracerebroventricular administration. Most effects of methoctramine (1.0 mM), which blocks presynaptic m2 and m4 receptors, were initially strong but then diminished over hours. Methoctramine produced a significant increase only in out/in ratio and out-of-field rate, whereas it tended to increase in-field rate and monotonically decrease smoothness. Pirenzepine (3.0 mM), which blocks postsynaptic m1 receptors, produced a significant increase only in out/in ratio, whereas it tended to increase out-of-field rate and decrease in-field rate; all these effects were monotonic with respect to time. A mixture of methoctramine plus pirenzepine recapitulated the place-cell effects of scopolamine, although neither the mixture nor its separate components affected behavior. We conclude that the effects of scopolamine on place cells likely result from a combination of blockade of postsynaptic m1 receptors, leading to reduced excitability, with blockade of presynaptic m2 and m4 receptors, leading to increased out-of-field firing.