Fraser A.W. Wilson

A microelectrode drive for long term recording of neurons in freely moving and chaired monkeys.

An electrode drive is described for recordings of neurons in freely moving and chaired monkeys during the performance of behavioural tasks. The electrode drives are implanted for periods of up to 6 months, and can advance up to 42 electrodes using 14 independent drive mechanisms. The drive samples 288 points within a 12 mmx12 mm region, with 15 mm of electrode travel. Major advantages are that recordings are made in freely moving monkeys, and these recordings can be compared with those in chaired experiments; waveforms of single neurons are stable, enabling prolonged recordings of the same neurons across periods of days; recordings can be made throughout the brain, including the dorsolateral prefrontal cortex and hippocampus; the drive accommodates both sharp microelectrodes and fine wire assemblies such as tetrodes.

Making your next move: Dorsolateral prefrontal cortex and planning a sequence of actions in freely moving monkeys

Prefrontal damage disrupts planning, as measured by disorders of the activities of daily living (Humphreys & Forde, 1998; Shallice & Burgess, 1991). In a monkey model of this form of planning, a variant of the delayed alternation task was performed by freely moving monkeys. In a 16×16-ft. testing room, four feeders were located in the middle of each wall. In the north task, monkeys alternated between feeders: west-north-east-north-west, and so forth. In the south task, the alternation sequence was east-south-west-south-east, and so forth. Neuronal activity was recorded during walking along the eight paths, constituting the north and south tasks. To succeed, monkeys had to memorize the alternation rule and monitor both their place in the sequence and the previously made spatially directed action before deciding to walk to a new location to the left or right of the current location. Responsive dorsolateral prefrontal neurons are strikingly selective. Sustained neuronal activity reflects the spatial direction of an ongoing or upcoming response. It is important that such selective responses occur in one but not both tasks, even though the movements are exactly the same in both tasks and at each location. We suggest that selective neuronal activity is tuned through learning and reflects the fundamental units of a planning mechanism: Individual neurons encode specific components of a sequence of behavioral actions and their temporal order. Populations of such neurons represent all the steps necessary to perform the north and south tasks. The sustained activity of these neurons suggests that planning and working memory mechanisms are integrated.

Ketamine affects memory consolidation: Differential effects in T-maze and passive avoidance paradigms in mice

The effects of ketamine, an N-methyl-D-aspartate (NMDA) antagonist, on memory in animals have been limited to the sub-anesthetic dose given prior to training in previous studies. We evaluated the effects of post-training anesthetic doses of ketamine to selectively manipulate memory consolidation, and the effect of pre-retention sub-anesthetic doses of ketamine on memory retrieval in passive avoidance and T-maze tasks in mice. Repeated post-training anesthetic doses of ketamine impaired the consolidation of memory in the T-maze but not in passive avoidance paradigms. This impairment was not permanent but diminished 1-2 days after ketamine withdrawal. Sub-anesthetic post-training doses of ketamine (5 mg/kg) had no effect on memory consolidation, and larger doses (10, 20 and 50 mg/kg) did not influence the retrieval of memory in the T-maze. The data suggest that repeated anesthetic doses of ketamine block NMDA receptors and affect memory consolidation. Moreover, NMDA mechanisms antagonized by ketamine appear to be selectively involved in spatial (T-maze) memory mechanisms but may not be necessary for non-spatial (passive avoidance) memory consolidation.

Dynamic changes in orbitofrontal neuronal activity in rats during opiate administration and withdrawal

The orbitofrontal cortex is involved in the reinforcing effects of drugs of abuse. However, how the dynamic activity in OFC changes during opiate administration and withdrawal period has not been investigated. We first tested the effects of opiates and drug craving with the conditioned place preference paradigm, using manganese-enhanced magnetic resonance imaging and traditional electroencephalograph recording techniques in rats. T1-weighted 2D MRI (4.7 T) was used after unilateral injection of MnCl(2) (200 nL, 80 mM) into the right orbitofrontal cortex. The manganese-enhanced magnetic resonance imaging data suggested that the OFC activity decreased during the opiate administration period but recovered increasingly during the withdrawal period. Also, we found decreases and increases in gamma-band (20-100 Hz) activity during the opiate administration and withdrawal period, respectively. Our results showed that orbitofrontal cortex activity decreased during morphine administration and then went up progressively over several days during withdrawal. The time course of the recovery of orbitofrontal activity from inhibition during the withdrawal period may be related to the experience of drug craving.

Effects of extremely low-frequency electromagnetic fields on morphine-induced conditioned place preferences in rats

In the present study, we examined the effects of extremely low-frequency (ELF) electromagnetic fields on morphine-induced conditioned place preferences in rats. During the conditioning phase (12 days), three groups of rats were placed in a sensory cue-defined environment paired with morphine (10mg/kg, i.p.) following exposure to either 20 Hz (1.80 mT) or 50 Hz (2.20 mT) or sham electromagnetic fields for 60 min/day, respectively, and were placed in another sensory cue-defined environment paired with physiological saline (1 ml/kg, i.p.) without exposure to electromagnetic fields. After finishing 12 days of conditioning, preference tests for the morphine-paired place were performed during a 10-day withdrawal period. The exposure to electromagnetic fields substantially potentiated morphine-induced place preferences in rodents, suggesting that ELF electromagnetic fields can increase the propensity for morphine-induced conditioned behaviors.

Spatially directed movement and neuronal activity in freely moving monkey

The abilities to plan a series of movements and to navigate within the environment require the functions of the frontal and ventromedial temporal lobes, respectively. Neuropsychological studies posit the existence of egocentric (prefrontal) and allocentric (ventromedial temporal) spatial frames of reference that mediate these functions. To examine neural mechanisms underlying egocentric and allocentric guidance of movement, we have developed behavioral and neurophysiological techniques for freely moving monkey. In this chapter, we provide evidence that the dorsolateral prefrontal cortex is important for egocentric spatial tasks in both the visual and tactile modalities, but it does not contribute to performance of an allocentric spatial task. Moreover, neurophysiological recordings indicate that prefrontal neurons are involved in monitoring the spatial nature of behavioral sequences in an egocentric memory task. In contrast, hippocampal neurons are active during spatially directed locomotion, apparently reflecting the monkeys location in a testing room. This discharge is independent of the tasks contingencies.

Effects of scopolamine on morphine-induced conditioned place preference in mice.

It is well known that the cholinergic system plays a crucial role in learning and memory. Psychopharmacological studies in humans and animals have shown that a systemic cholinergic blockade may induce deficits in learning and memory. Accumulated studies have indicated that learning and memory play an important role in drug addition. In the present study, in order to get a further understanding about the functions of the cholinergic system in drug‐related learning and memory, we examined the effects of scopolamine (0.5, 1.0 and 2.0 mg/kg) on morphine‐induced conditioned place preference (CPP). Two kinds of morphine exposure durations (4 days and 12 days) were used. The main finding was that all doses of scopolamine enhanced the extinction of morphine‐induced CPP in mice treated with morphine for 12 days. However, in mice treated with morphine for 4 days, all doses of scopolamine did not inhibit morphine‐induced CPP. The highest dose (2.0 mg/kg) of scopolamine even significantly delayed the extinction of morphine‐induced CPP. Our results suggest that the effects of a systemic cholinergic blockade on morphine‐induced CPP depend on the morphine exposure time.

The dynamics of hippocampal sensory gating during the development of morphine dependence and withdrawal in rats

The effects of morphine on hippocampal sensory gating (N40) during the development of morphine dependence and withdrawal were investigated in the double click auditory evoked potential (EP) suppression paradigm. Rats were made dependent upon morphine hydrochloride by a series of injections (every 12 h) over 6 days, followed by withdrawal after stopping morphine administration. Hippocampal gating was examined during the development of dependence and withdrawal. Moreover, the DA antagonist haloperidol was used to assess the contribution of dopamine to hippocampal gating induced by morphine. Our results showed that the morphine-treated rats exhibited significantly disrupted hippocampal gating during the development of morphine dependence and this disrupted gating was partially reversed by haloperidol pretreatment. In contrast, there was significantly enhanced hippocampal gating at the fifth and sixth days of withdrawal. The dynamics of hippocampal gating during the development of morphine dependence and withdrawal suggests the interaction between the hippocampus and opioids.

EEG activities in the orbitofrontal cortex and dorsolateral prefrontal cortex during the development of morphine dependence, tolerance and withdrawal in rhesus monkeys.

Investigating the activities of the prefrontal cortex (PFC) in the process of addiction is valuable for understanding the neural mechanism underlying the impairments of the PFC after drug abuse. However, limited data are obtained from primate animals and few studies analyze Electroencephalogram (EEG) in the gamma band, which plays an important role in cognitive functions. In addition, it is yet unclear whether drug abuse affects the orbitofrontal cortex (OFC) and dorsolateral PFC (DLPFC)--the two most important subregions of the PFC--in similar ways or not. The aim of this study is to address these issues. We recorded EEG in the OFC and DLPFC in three rhesus monkeys. All animals received a course of saline (NaCl 0.9%, 2 ml) injection (5 days) followed by 10 days of morphine injection (every 12 h), and then a further series of saline injection (7 days). A main finding in the present study was that morphine decreased EEG power in all frequency bands in a short period after injection in both the OFC and DLPFC in monkeys. And gamma power decreased not just in a short period after morphine injection but lasted to 12 h after injection. Moreover, we found that although the changes in EEG activities in the OFC and DLPFC at 30-35 min after injection were similar, the DLPFC was more sensitive to the effect of morphine than the OFC.

The egocentric spatial reference frame used in dorsal–lateral prefrontal working memory in primates

The dorsal-lateral prefrontal cortex (dlPFC) has been proposed to be the site of spatial working memory (WM), and this concept has had a profound influence on functional studies of the prefrontal cortex (PFC). The concept of spatial WM has been understood to mean that the location of an object is memorized for a short period of time. However, this concept of space is a simplification. To process the spatial information, different spatial frames can be used. In this review, the authors present data from their own laboratory to argue that the dlPFC is related to the egocentric spatial information processing (ESIP) in WM. The goal of this review is to introduce and discuss the egocentric spatial reference frame (ESRF) located in the dlPFC. The ESIP in the PFC might be involved in self-recognition.