Robert J. Douglas

The Development of Hippocampal Function: Implications for Theory and for Therapy

One thesis of this chapter is that the hippocampus may have two different but related modes of functioning. The simpler of the two, present in infancy and at times in adulthood, consists of a gross or nonspecific inhibition of emotional reactivity in general. The generation of nonspecific inhibition requires only that the hippocampal pyramidal cells be functionally developed and that they be driven by some synchronized input such as the θ-pacing system. The second functional mode is called “stimulus-specific inhibition” because it corresponds to a specific inhibition of an emotional reaction to a particular stimulus or set of stimuli. Stimulus-specific inhibition can be carried out only when the hippocampal pyramidal cells are “informed” of the stimulus via the temporoammonic tract and its major target, the dentate gyrus. The specific form of inhibition is at best only rudimentarily developed at birth and develops in synchrony with the maturation of the dentate gyrus. The development of stimulus-specific inhibition, it will be argued, is interfered with by early stressful i experience. The harmful effects of early stress on adult behavior appear to be counteracted by drugs which enhance cholinergic transmission.

Olfactory lesions, emotionality and activity ☆

Abstract Female rats with bilateral or unilateral lesions of the olfactory bulbs were rated for emotionality and tested on several measures of spontaneous activity. Bilateral lesions resulted in hyperemotionality similar in kind, and in some cases degree, to the rage produced by septal lesions. Except for some effects which were probably due to emotionality, the spontaneous behavior of rats with olfactory lesions was well within a normal range, and distinctly different from that of septally lesioned rats.

The ontogeny of a hippocampus-dependent response in two rodent species

Spontaneous alternation, a form of unlearned behavior which is related to inhibition, the hippocampus, and the cholinergic system, was studied ontogenetically in rats and guinea pigs. Although there was considerable individual variability, the typical rat first began to display alternation behavior at about 27–28 days of age. In the guinea pig alternation was above chance even in the first week of life and fully adult rates were found in all subjects 10 days old or older. These ages are highly comparable to those reported for the maturation of the granule cells of the dentate gyrus of the hippocampus in these species ( Altman and Das, 1965 , Altman and Das, 1967 ). The present findings thus support the postulate of those authors that the hippocampus does not function in an adult manner until the differentiation of these neurons is essentially complete. The present rat results are in close agreement with those of several other studies of the ontogeny of hippocampus-dependent behavior and with two studies of the development of the adult reaction to cholinolytic and cholinomimetic drugs. Evidence was presented suggesting that in some of the more emotionally reactive subjects the early handling and/or testing may have retarded hippocampal development.

Parallel but independent effects of pentobarbital and scopolamine on hippocampus-related behavior

In Wistar-derived rats subanesthetic doses of pentobarbital were found to abolish spontaneous alternation, a form of exploratory behavior selectively sensitive to hippocampal damage and (until now) anticholinergic drugs. A dose of 15 mg/kg of pentobarbital completely abolished the behavior, as did a scopolamine dose of 0.3 mg/kg. Dose-response curves for the two drugs could be closely superimposed on the assumption that the potency ratio was about 45:1. Combined injections of the two drugs, with each employed at barely subthreshold dosage, did not reliably reduce the alternation rate, although a superthreshold combination of the two drugs did completely abolish alternation. All effects were predicted on the basis of electrophysiological-pharmacological studies showing each drug to affect hippocampal electrical activity in a different way. Pentobarbital, scopolamine, and massive hippocampal lesions have now been found to have the same behavioral effects on at least five different and highly diagnostic responses.

Angle between choice alleys as a critical factor in spontaneous alternation

Rats were tested for spontaneous alternation in a variety of mazes differing in the angle between choice alleys. Uniformly high alternation rates were found at all angles from 330 down to 90 deg. At 45 or 0 deg, the rates approximated a chance 50%, and at angles between 45 and 90 deg the alternation rates were also intermediate. The hypothesis that the spatial distance between goal regions is the critical factor was rejected, and it was concluded that the angle between alleys is the principal factor determining alternation under these conditions. The results support the idea that alternation in the rat is basically a vestibular phenomenon.

Spontaneous Alternation Behavior and the Brain

One strategy for writing this chapter would have been to prepare an immense list of all studies linking spontaneous alternation behavior to brain lesions or drugs. Our minds thoroughly boggled, we could then have identified a few missing items in the list and agreed that further research was necessary. I believe, however, that even though there are many studies crying out to be done, it is possible to make considerable sense out of the staggering amount of evidence already in existence. The results of hundreds of alternation experiments do tell a story—two quite different stories, in fact. And these stories reveal more than why a rat turns right or left in a T maze. The alternating rat is trying to tell us how the brain works, and my intent in writing this chapter is to convey to you what the alternating rat tells me.

Spontaneous alternation as a function of maze configuration

The tendency of the rat to alternate spontaneously was examined in mazes of different shapes. A typical 86.1% rate of alternation occurred in the T-maze, but the rate of 55.6% found in a maze with choice alleys side by side did not exceed chance. An even lower rate was found in a pilot study employing the latter maze. It was suggested that the crucial factor in spontaneous alternation is the spatial distinctiveness of the choice alleys and that alternation is not simply a matter of a choice between two alleys. The side-by-side maze configuration could be profitably employed as an alternative to the T-maze in learning studies in which spatial cues and/or alternation tendencies are confounding factors which bias either “learning speed” or group differences when one group differs from the other in either factor above.

Effects of aging on formalin-fixed brain weight in mice and rats.

In three mouse lineages it was found that during the 18- to 60-day interval after formalin fixation, brain weight was inversely proportional to the age at sacrifice, as was the decline in the weight of the brain during this period. In a second study using rat subjects it was confirmed that the aging difference is due to a reduction, in old age, of the swelling reaction of the brain when first placed in a formalin solution. It was suggested that this easily measured phenomenon might be employed as an operational index of brain aging.

Using SAB as a Tool: Advice from a Veteran

In reviewing the literature for my previous chapter in this book (Chapter 5), I was struck by the difference between the 1980s and the “heyday” of alternation studies in the 50s and 60s. First, there are now very few studies being done on this topic at all. I believe that one important reason for this is the shift to the radial maze by people who would have studied alternation in the past and who in many cases are repeating old alternation studies with a different apparatus. The radial maze measures basically the same underlying processes as alternation, but in an inefficient manner. That is, in an eight-arm radial maze it is not until the sixth trial that entering a new alley becomes improbable by chance alone. Further, it is possible for a rat to be very successful in a radial maze by adopting a circling strategy, and I have personally seen that many rats do just that. Having used both tasks, I believe that the standard SAB paradigm is more efficient and valid and that the radial maze could be more profitably employed by rewarding rats for entering a given alley rather than for avoiding it. That is, the rat would be started from a different, randomly chosen, alley on each trial and rewarded for going to a given location in space. In that way the first response would contain almost three bits of information instead of almost zero. With this procedure one would no longer be measuring curiosity but would be efficiently investigating a mechanism, spatial orientation, that is importantly involved in alternation.

Hippocampal Theta and Disinhibition: A Counterreply

Evidence was presented against an argument by Bennett (1969) that hippocampal lesions result in a deficit in simple 2-choice discrimination learning and/or delayed responding. It was shown that behavioral evidence suggests that hippocampal theta waves may be an index of behavioral disinhibition.