Neil McNaughton

Supramammillary cell firing and hippocampal rhythmical slow activity.

Extracellular multi-unit activity was recorded from sites in the supramammillary area of urethane anaesthetized rats, while simultaneously recording the hippocampal EEG. The pattern of supramammillary area cell discharge was found to be rhythmic and in phase with concurrent hippocampal rhythmical slow activity (RSA). Septal application of procaine (20%, 1-5 microliters), that abolished hippocampal RSA, did not abolish the rhythmicity of supramammillary cell firing. These data suggest that the frequency of hippocampal RSA may be determined in the supramammillary area rather than in the medial septum as has previously been supposed.

Elicited hippocampal theta rhythm: a screen for anxiolytic and procognitive drugs through changes in hippocampal function?

Hippocampal damage produces cognitive deficits similar to dementia and changes in emotional and motivated reactions similar to anxiolytic drugs. The gross electrical activity of the hippocampus contains a marked ‘theta rhythm’. This is a relatively high voltage sinusoidal waveform, resulting from synchronous phasic firing of cells, variation in which correlates with behavioural state. Like the hippocampus, theta has been linked to both cognitive and emotional functions. Critically, it has recently been shown that restoration of theta-like rhythmicity can restore lost cognitive function. We review the effects of systemic administration of drugs on hippocampal theta elicited by stimulation of the reticular formation. We conclude that reductions in the frequency of reticular-elicited theta provide what is currently the best in-vivo means of detecting antianxiety drugs. We also suggest that increases in the power of reticular-elicited theta could detect drugs useful in the treatment of disorders, such as dementia, that involve memory loss. We argue that these functionally distinct effects should be seen as indirect and that each results from a change in a single form of cognitive–emotional processing that particularly involves the hippocampus.

Coupling of Theta Oscillations between Anterior and Posterior Midline Cortex and with the Hippocampus in Freely Behaving Rats

Theta oscillations in the hippocampus support cognitive processing. Theta-range rhythmicity has also been reported in frontal and posterior cortical areas--where it tends to show consistent phase-relations with hippocampal rhythmicity. Theta-range rhythmicity may, then, be important for cortico-cortical and/or cortico-hippocampal interactions. Here, we surveyed the rat frontal and posterior midline cortices for theta-related oscillations and examined their relationships with hippocampal activity in freely moving rats. Variation in electroencephalography across 4 general classes of spontaneous behavior demonstrated different profiles of theta-like activities through the rat midline cortices. Analysis of cortico-cortical and cortico-hippocampal coherences showed distinct, behavior-dependent, couplings of theta and delta oscillations. Increased theta coherence between structures was most obvious during nonautomatic behaviors and least during immobility or grooming. Extensive coupling of theta oscillations throughout the rat midline cortices and hippocampus occurred during rearing, and exploratory behavior. Such increases in coherence could reflect binding of cortico-hippocampal pathways into temporary functional units by behavioral demands. Extensive coupling of frontal delta, which lacked coherence with posterior areas (including the hippocampus), suggests that different frequencies of rhythmicity may act to bind groups of structures into different functional circuits on different occasions.

Low dose scopolamine affects discriminability but not rate of forgetting in delayed conditional discrimination

The effect of scopolamine on remembering was examined in a delayed conditional discrimination procedure with rats. Remembering was quantified by a negative exponential function fitted to estimates of discriminability derived from a signal detection type of analysis. This function had two parameters: a measure of initial discriminability of the sample stimuli in the absence of a memory requirement (at zero delay) and a measure of rate of forgetting. Eight rats were trained on an auditory delayed conditional discrimination task until they were showing stable performance. Each rat then received doses of 0, 0.005, 0.014, 0.042, 0.125 and 0.375 mg/kg scopolamine IP in a saline vehicle. There was a highly significant, largely linear, decrease in initial discriminability. This was obvious even at the lowest dose of scopolamine. Poorer memory, as demonstrated by an increase in b, was only apparent at the highest dose. Significant changes in per cent of correct responses were also only obtained at higher doses. These results show that initial discriminability and rate of forgetting are pharmacologically as well as theoretically independent. They suggest that the measure of initial discriminability used here is a particularly sensitive measure of at least some types of cholinergic dysfunction; and they also suggest that effects of scopolamine in other working memory tasks could be more a result of changed stimulus processing than of impairment of memorial processes.

The Reinforcement Sensitivity Theory of Personality: The neuropsychology of fear and anxiety: a foundation for Reinforcement Sensitivity Theory

Personality factors, as normally studied, are sources of variation that are stable over time and that derive from underlying properties of an individual more than current changes in their environment. They account for behavioural differences between individuals presented with identical environments that show consistent patterns within that individual across time. As such, an ultimate goal of personality research must be to identify the relatively static biological variables that determine the superficial factor structure evident in behaviour and other measures. This is not to deny the importance of the environment in controlling personality. But, to produce consistent long-term effects, environmental influences must be mediated by, and instantiated in, biological systems. Biology can also be viewed as more fundamental in that environmental events (such as an impact to the front of the head) have permanent effects on personality not in relation to the external parameters of the event (such as the force of impact) but rather in relation to the precise extent of change the event induces in the brain. Those interested in individual variation in the tendency to neurotic disorders have been particularly inclined to theorize in terms of either the real or the conceptual nervous system. Pavlov saw variation in the response of his dogs to both traumatic and everyday events as arising from the ‘Strength of the Nervous System’ – a purely theoretical construct, albeit with a consistent behavioural structure (Gray 1964, 1967).

The medial supramammillary nucleus, spatial learning and the frequency of hippocampal theta activity.

Previous studies have shown that the presence of hippocampal theta activity (theta) is important for learning and that the medial supramammillary nucleus (SuM) is involved in the control of the frequency of theta. In the present experiments, a single-day version (20 trials) of the Morris water maze was used to investigate the effects of drug injections into SuM on hippocampal theta frequency and spatial learning. Two groups of rats received an injection of chlordiazepoxide (CDP, 0.5 microl, 40 microg/microl) or saline (0.5 microl) into SuM 10 min before training in the Morris water maze. Two other groups of rats received an i.p. injection of 5 mg/kg CDP or saline, and two further groups received short (10 min) or long (15 min) immersion in cool water (22 degrees C) before training. The results showed: (1) in all groups theta frequency was an inverse logarithmic function of training time; (2) systemic CDP or long cool water exposure decreased theta frequency to a greater extent (by 1 Hz), and also impaired learning to a greater extent, than the other treatments; (3) that SuM-CDP produced a modest decrease in theta frequency (0.35-0.5 Hz) and a modest impairment of spatial learning. These data suggest that theta frequency per se may be important for spatial learning and that total abolition of theta is not necessary for dysfunction; and that while a lesser part of the effect of i.p. CDP on spatial learning appears to be mediated by SuM the greater part appears to involve other nuclei as well.

Effects of the NMDA antagonists CPP and MK-801 on delayed conditional discrimination

N-methyl-D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined.

The role of the medial supramammillary nucleus in the control of hippocampal theta activity and behaviour in rats

The medial supramammillary nucleus (mSUM) controls the frequency of hippocampal theta activity, completely in anaethsetized rats and partially in free‐moving rats. mSUM could therefore influence hippocampal contributions to cognition and emotion. Using chemical lesions of mSUM in rats, we tested whether mSUM is involved in controlling several hippocampal‐dependent functions: (i) defensive behaviour (open field, fear conditioning); (ii) behavioural inhibition (fixed interval schedule, differential reinforcement of low rates schedule); and (iii) spatial learning (water maze). Theta frequency was measured in all these tasks. mSUM lesions produced a pattern of changes in motivated/emotional behaviours (hyperactivity in defensive and operant tasks) similar to the pattern produced by hippocampal lesions, but had no significant effect on spatial learning. mSUM lesion decreased theta frequency modestly (by ≈ 0.4 Hz) in behaving rats if the amount of movement was unchanged. There was not always a parallel between changes in theta frequency and behaviour; behaviours changed despite unchanged theta in defensive tasks and learning changed little despite a lower frequency of theta in the water maze task. This suggests that mSUM function impacts on emotional behaviour more than cognition, and can modulate theta and behaviour independently.

Differences in synaptic transmission between medial and lateral components of the perforant path

The differences between the potentials recorded in the hilus of the dentate gyrus following test shocks applied separately to the medial perforant path (MPP) and the lateral perforant path (LPP) have been ascribed to the greater length of dendrite over which the LPP potentials are electrotonically conducted to the somata of the granule cells. We tested this hypothesis by recording MPP and LPP evoked potentials in the hilus and in the molecular layer of both in vivo and in vitro preparations. Analysis of field potential and current source density depth profiles in vivo indicated that different waveshapes occurred not only in the hilus but at the sites of synaptic contact in the molecular layer as well. In the in vitro study, paired stimulating and recording electrodes were stepped through the molecular layer and revealed a relatively sudden waveshape change around 225 micron from the cell layer, where the transitional zone between MPP and LPP terminal fields was expected to be located. Quantitative analysis of the differences between the potentials recorded in the molecular layer and the hilus revealed that electrotonic decay accounts for approximately 20% of the difference seen in the hilus between the MPP and LPP potentials. Our data therefore suggest that the differences between MPP and LPP hilar potentials are due mostly to differences between the two pathways in their properties of synaptic transmission and are due relatively little to the different sites of synaptic contact on the dendritic tree.

Neurochemically dissimilar anxiolytic drugs have common effects on hippocampal rhythmic slow activity

Previous experiments have shown that anxiolytic drugs reduce the frequency of hippocampal rhythmic slow activity, induced by high frequency stimulation of the reticular formation and flatten the function relating threshold septal stimulation to the frequency of driven rhythmic slow activity. All of the drugs involved are known to augment GABAergic transmission. The present experiments investigated the effects of the novel anxiolytic compound buspirone which, unlike conventional anxiolytics, does not interact with GABA, yet is a clinically effective anxiolytic. Buspirone (0.156-40 mg/kg, i.p.) was found to reduce the frequency of reticular-elicited rhythmic slow activity, in a similar manner to chlordiazepoxide (0.019-20 mg/kg, i.p.). Buspirone did not change the linearity of the voltage-frequency function. Buspirone (10 mg/kg, i.p.) also altered the threshold for septal driving of rhythmic slow activity, in a similar manner to classical anxiolytics. The combination of chlordiazepoxide (5 mg/kg, i.p.) with corticosterone (0.2 mg, s.c.) removed the minor differences between buspirone and chlordiazepoxide in both the septal and reticular tests. These results show that buspirone altered the control of rhythmic slow activity in the hippocampus, in a manner which appeared functionally equivalent to other anxiolytics but which depends on mechanisms which are likely to be neurally and pharmacologically distinct from those of other anxiolytic drugs.