Crossed unilateral lesions of the medial forebrain bundle and either inferior temporal or frontal cortex impair object–reward association learning in Rhesus monkeys

Abstract

In an accompanying paper we showed that combined transection of the fornix, amygdala and temporal stem in monkeys produced dense amnesia, including an impairment in visual object–reward association learning. We proposed that this combined surgical section had its effect by isolating temporal cortex from the ascending projections of the basal forebrain and midbrain structures. To test this hypothesis, in the present experiment we disconnected the inferior temporal cortex from these basal forebrain and midbrain structures, while sparing cortical white matter, by crossed unilateral lesions of the medial forebrain bundle in one hemisphere and inferior temporal cortex in the opposite hemisphere. The aim of the medial forebrain bundle lesion was to section axons of cells, both those that project to the cortex via the medial forebrain bundle, and those which control the activity of these same structures. A single unilateral lesion alone had no effect on the ability to learn and remember visual object–reward associations, but the crossed unilateral lesions produced an impairment in this task which was equal in severity to the impairment seen earlier after bilateral section of the fornix, amygdala and temporal stem. The impairment was not an effect of interrupting fibres to the cortex from the ventromedial hypothalamus, or of unilateral sensory neglect. This supports the hypothesis that these midbrain and basal forebrain afferents to the inferior temporal cortex are important for new visual learning. Furthermore, an impairment of equal severity was demonstrated in a separate group of animals that received crossed unilateral lesions of the medial forebrain bundle in one hemisphere and of the frontal cortex in the opposite hemisphere. We propose that the frontal cortex acts to modulate basal forebrain activity which in turn reinforces object representations in the inferior temporal cortex during learning.

Introduction

In the accompanying paper, Gaffan et al. [18] demonstrated that bilateral transection of the fornix, amygdala and temporal stem leads to a dense anterograde amnesia in monkeys. It was proposed that this amnesia resulted from the interruption of projections from structures of the basal forebrain and midbrain to the temporal cortex, which are known to project through the three pathways sectioned in the behavioural experiments [18]. This combined lesion of Gaffan et al. will necessarily involve some disruption of pathways other than those from the basal forebrain and midbrain to the temporal lobe. However, comparison with other behavioural data, such as the largely negative effects of uncinate fascicle section on tasks other than visually cued conditional tasks [8], [21] suggests that it was the interruption of afferents to the temporal lobe from subcortical structures which caused dense amnesia in the animals reported earlier [18]. The purpose of the present experiment was to test this hypothesis further.

The cortical interactions with the basal forebrain and midbrain structures considered important by Gaffan et al. [18] are complicated, since these subcortical structures have not only direct projections to the temporal lobe, but also many reciprocal interactions with each other, such that the activity of one subcortical structure may be influenced by any other. Selective lesions of any one of these subcortical structures, or any combination, is an impractical way in which to address the hypothesis initially, because we do not know which of these cell groups, or combination of cell groups, is important for memory in monkeys. Experiments using selective lesions of the cholinergic cells of the basal forebrain have provided evidence both for [12], [32] and against [3], [4], [5] a role in learning. The dopaminergic cells of the midbrain have been shown to be responsive to reward [22] and have been proposed to play a part in reward learning and related behaviour [22], [33]. In the rat, combined blockade of both the cholinergic and serotonergic systems has been shown to result in a severe learning impairment [36], [37]. An appropriate way to test the hypothesis of Gaffan et al. [18], initially, is to disrupt the activity of a large number of these basal forebrain and midbrain structures, while sparing the cortical white matter which is damaged in the lesions of Gaffan et al.

Many corticopetal axons from the basal forebrain and midbrain structures project through the medial forebrain bundle on their way to the cortex, and also interconnect with each other. For example, cells which project to the cortex via the medial forebrain bundle include those dopaminergic cells of the ventral tegmental area and substantia nigra, the noradrenergic cells of the locus coeruleus and seroternegic cells of the Raphe nucleus [27]. In addition to these projections, the medial forebrain bundle contains numerous other fibres containing neurotransmitters such as histamine, substance P, VIP, CCK, neurotensin, ACTH and enkephalin [27]. In addition to their direct action on the cortex, many axons originating in the basal forebrain and midbrain, and travelling through the medial forebrain bundle, may serve to modulate the activity of other cortically projecting areas such as the substantia nigra, or the substantia innominata [6]. If the hypothesis of Gaffan et al. [18] is correct, then a lesion that interrupts axons within the medial forebrain bundle, should have a similar effect on the ipsilateral temporal cortex as a combined transection of fornix, amygdala and anterior temporal stem.

Bilateral lesions of the medial forebrain bundle produce a syndrome of adipsia and aphagia [25], making the effect of bilateral lesions on memory difficult to determine. Therefore, lesions of the medial forebrain bundle were made in one hemisphere with a unilateral ablation of the inferior temporal cortex in the opposite hemisphere. In this case, only the interactions between the basal forebrain and midbrain structures which project through (or whose activity is controlled by projections through) the medial forebrain bundle and the inferior temporal cortex were lost in both hemispheres. The monkeys were tested on visual object–reward association learning, a task which is severely impaired in monkeys with combined surgical section of the fornix, amygdala and anterior temporal stem [18]. If a similar impairment is seen in the present experiment in animals with the crossed unilateral ablations of the medial forebrain bundle and the inferior temporal cortex, then this would support the hypothesis put forward by Gaffan et al. A lack of impairment in the current experiment would suggest, contrary to the hypothesis of Gaffan et al., that the isolation of the temporal cortex from its basal forebrain and midbrain afferents is not the cause of the dense amnesia seen in their experiment.

The task used in the present experiment (object–reward association learning) is severely impaired in monkeys with bilateral ablations of either the inferior temporal cortex [20] or the frontal cortex [30]. Therefore, the interaction of the basal forebrain and midbrain in the current experiment was investigated with not only disconnections from the inferior temporal cortex, but also the frontal cortex. This interaction was investigated by use of a group of monkeys in which a lesion of the medial forebrain bundle was made in one hemisphere and a frontal cortex ablation in the opposite hemisphere, so that only the interactions between the basal forebrain and midbrain structures which project through (or whose activity is controlled by projections through) the medial forebrain bundle and the frontal cortex were lost in both hemispheres.

To interrupt axons of the medial forebrain bundle, which is not amenable to open neurosurgery, we used a stereotaxically guided electrode whose tip was heated by a radiofrequency current to a known temperature. One of the animals (IT2) received a lesion aimed at just one antero-posterior level of the medial forebrain bundle at the level of the lateral hypothalamus, while the other animals all received lesions that were intended to damage 4 mm in antero-posterior extent of the medial forebrain bundle (at the level of the lateral hypothalamus). We also made control lesions in two animals. These animals received unilateral ablation of the inferior temporal cortex in one hemisphere and a lesion of the ventromedial hypothalamus, instead of the medial forebrain bundle in the other hemisphere. A lack of behavioural impairment in these animals would indicate that any effect of the medial forebrain bundle lesion is not an effect of disruption to the ventromedial hypothalamus.