Fornix-transected Monkeys Research Articles

Structural Connectivity Changes After Fornix Transection in Macaques Using Probabilistic Diffusion Tractography.

The fornix, the limbic system's white matter tract connecting the extended hippocampal system to subcortical structures of the medial diencephalon, is strongly associated with learning and memory in humans and nonhuman primates (NHPs). Here, we sought to investigate alterations in structural connectivity across key cortical and subcortical regions after fornix transection in NHPs. We collected diffusion-weighted MRI (dMRI) data from three macaque monkeys that underwent bilateral fornix transection during neurosurgery and from four age- and cohort-matched control macaques that underwent surgery to implant a head-post but remained neurologically intact. dMRI data were collected from both groups at two time points, before and after the surgeries, and scans took place at around the same time for the two groups. We used probabilistic tractography and employed the number of tracking streamlines to quantify connectivity across our regions of interest (ROIs), in all dMRI sessions. In the neurologically intact monkeys, we observed high connectivity across certain ROIs, including the CA3 hippocampal subfield with the retrosplenial cortex (RSC), the anterior thalamus with the RSC, and the RSC with the anterior cingulate cortex (ACC). However, we found that, compared to the control group, the fornix-transected monkeys showed marked, significant, connectivity changes including increases between the anterior thalamus and the ACC and between the CA3 and the ACC, as well as decreases between the CA3 and the RSC. Our results highlight cortical and subcortical network changes after fornix transection and identify candidate indirect connectivity routes that may support memory functions after damage and/or neurodegeneration.

Adaptability to changes in temporal structure is fornix-dependent.

Recognition memory deficits, even after short delays, are sometimes observed following hippocampal damage. One hypothesis links the hippocampus with processes in updating contextual memory representation. Here, we used fornix transection, which partially disconnects the hippocampal system, and compares the performance of fornix-transected monkeys with normal monkeys on two versions of a delayed-matching-to-position task with short delays. Spatial recognition memory was affected by fornix transection only when the temporal structure of the task changed across trials, while differences in motor control, motivation, perception, or short-term memory were not critical. We attributed the deficit to a compromised ability in tracking changes in task temporal structure.

Role of the hippocampal system in associative learning beyond the spatial domain.

Expert opinion remains divided on the issue of whether the hippocampal system functions exclusively in spatial information processing, e.g. in navigation or in understanding spatial relations, or whether it plays a more general role in higher brain function. Previous work on monkeys and rats has tended to support the former view, whereas observations in the clinic point to the latter, including functions as diverse as declarative knowledge, episodic memory, word learning, and understanding relations among objects. One influential theory posits a general role for the hippocampal system in associative learning, with emphasis on associations learned rapidly and recently. The results presented here are consistent with this theory, along with previous clinical and theoretical studies indicating that the hippocampal system is necessary for associative learning even if no component of the association relies on spatial information. In the study reported here, rhesus monkeys learned a series of conditional stimulus-response associations involving complex visual stimuli presented on a video monitor. Each stimulus instructed one of three responses: tapping the stimulus with the hand, steady hand contact with the stimulus for a brief period of time, or steady contact for a longer time. Fornix transection impaired the learning of these associations, even though both the stimuli and the responses were nonspatially differentiated, and this deficit persisted for at least 2 years. This finding indicates that the hippocampal system plays an important role in associative learning regardless of the relevance of spatial information to any aspect of the association. Fornix-transected monkeys were impaired in learning new stimulus-response associations even when the stimuli were highly familiar. Thus, the deficit was one of associating each stimulus with a response, as opposed to problems in distinguishing the stimuli from each other. In contrast to these effects, fornix transection did not impair performance when familiar stimuli instructed a response according to an already-learned association, which shows that the deficit was one of learning new associations rather than one of retention or retrieval of previously learned ones. Taken together, these results show that fornix transection causes a long-lasting impairment in associative learning outside of the spatial domain, in a manner consistent with theories of hippocampal-system function that stress a general role in the rapid acquisition of associative knowledge.

Fornix transection impairs conditional visuomotor learning in tasks involving nonspatially differentiated responses.

Rhesus monkeys learned a series of conditional visuomotor associations involving two-dimensional "objects" that instructed one of three responses: tapping a touch screen, steady contact with the screen for a brief period, or steady contact for a longer period. Relative to controls, fornix-transected monkeys were impaired in the acquisition of new associations and in the retention of preoperatively learned ones. These findings challenge the view that the hippocampal system participates in associative learning only when spatial information is relevant to either the stimulus or the response.

Scene-Specific Memory for Objects: A Model of Episodic Memory Impairment in Monkeys with Fornix Transection

Abstract A series of five experiments investigated the relationship between object memory and scene memory in normal and fornix-transected monkeys. An algorithm created formally defined background and objects on a large visual display; the disposition of some particular objects in particular places in a particular background constitutes a formally defined scene. The animals learned four types of discrimination problem: (1) object-in-place discrimination learning, in which the correct (rewarded) response was to a particular object that always occupied the same place in a particular unique background, (2) place discrimination learning, in which the correct response was to a particular place in a unique background, with no distinctive object at that place, (3) object discrimination learning in unique backgrounds, in which the correct response was to a particular object that could occupy one or the other of two possible places in a unique background, and (4) object discrimination learning in varying backgrounds, in which the correct response was to a particular object that could appear at any place in any background. The severest impairment produced by fornix transection was in object-in-place learning. Fornix transection did not impair object discrimination learning in varying backgrounds. The results from the other two types of learning task showed intermediate severity of impairment in the fornix-transected animals. The idea that fornix transection in the monkey impairs spatial memory but leaves object memory intact is thus shown to be an oversimplification. The impairments of object memory in the present experiments are analogous to the impairments of episodic memory seen in human amnesic patients.

Normal forgetting, impaired acquisition in memory for complex naturalistic scenes by fornix-transected monkeys

As part of an earlier experiment three rhesus monkeys ( Macaca mulatta) with fornix transection and three normal control monkeys had learned to discriminate among 320 naturalistic complex scenes. The fornix-transected animals had been much slower than the controls to reach criterion in learning this task, but eventually did so. The present experiment measured long-term forgetting of these scenes. Seven weeks after reaching criterion each animal was retested. All animals showed some forgetting of the scene discriminations they had learned. The amount forgotten was equal in the two groups. These results show that the slower learning of the scenes following fornix transection was not caused by accelerated forgetting. The present findings in fornix-transected monkeys are similar to previous findings in human amnesic patients.

Restoration of learning ability in fornix-transected monkeys after fetal basal forebrain but not fetal hippocampal tissue transplantation

Monkeys with bilateral transection of the fornix were severely but selectively impaired on learning and retention of visuospatial conditional discriminations, visual conditional discriminations and non-conditional spatial-response tasks. Bilateral transplantation of cholinergic-rich fetal basal forebrain tissue into the hippocampus abolished significant learning impairments on all those tasks impaired by fornix lesions when tested three to nine months after transplantation whereas bilateral transplants of non-cholinergic fetal hippocampal tissue into hippocampus showed no such beneficial effect. Acetylcholinesterase staining was severely depleted throughout the dentate gyrus and hippocampus in fornixtransected monkeys compared with animals with control corpus callosum ablations. Staining was largely restored to normal in the host hippocampus and dentate gyrus in monkeys with cholinergic transplants, whereas acetylcholinesterase staining was abnormal in those with non-cholinergic grafts. These experiments suggest that where a “higher order” cognitive function, in this case the acquisition of specific types of information into long-term memory, is disturbed by a neuropharmacologically simple lesion, cognitive function can be restored by transplantation of neurons containing appropriate neurotransmitters.

Running recognition of configural stimuli by fornix-transected monkeys.

Six Rhesus monkeys were trained in a running recognition task with visual-spatial configurations as the stimuli to be remembered. Following pre-operative training half the monkeys were subjected to fornix transection and half to a control operation. Fornix transection produced a severe and apparently permanent impairment. These results add to the evidence that fornix transection produces defects in memory which cannot be explained as secondary consequences of impairments of perception.

Delayed matching by fornix-transected monkeys: the sample, the push and the bait.

In the acquisition event of ordinary delayed matching to sample the monkey sees a sample, displaces it, and finds a food reward underneath; subsequently the retention test consists of a choice between that sample and a distractor, and the strength of the memory laid down by the acquisition event may be assessed by the correctness of choice at the retention test. The present experiments varied the acquisition events and examined the effect of those variations on normal and fornix-transected monkeys' memory. One variation was to proceed as normally but never to bait the sample at acquisition; this variation allowed assessment of the role of the food reward in ordinary matching. Another was to present the sample, baited and to be displaced, as normally, but to present also the distractor, baited but not requiring to be displaced, in a second acquisition event; this “push–match” variation allowed assessment of memory for the displacement. The main result from normal monkeys was that matching to unbaited samples was learned much faster than matching to baited samples. Following fornix transection, final performance levels in matching to baited and to unbaited samples were unimpaired but push–match showed a permanent deficit. These results support earlier indications that fornix-transected monkeys have normal sensory memory but are deficient in the memory of instrumental responses.

Effects of fornix transection on spontaneous and trained non-matching by monkeys.

Three monkeys with fornix transection and three normal control monkeys performed a series of tasks which were variations of delayed non-matching. Experiment 1 showed that even at short retention intervals fornix transection impaired the spontaneous tendency to explore novel objects. Experiment 2 provided differential reward for non-matching and showed that the fornix-transected monkeys learned and performed non-matching normally even though the sample-match retention intervals were long throughout the experiment. Experiment 3 showed that non-matching performance was transiently more disrupted in fornix-transected than in normal monkeys when the testing procedure was changed, in a variety of ways, while maintaining the basic non-match rule. Experiment 4 required the monkeys to discriminate objects they had displaced from objects they had seen but not displaced; fornix transection produced in this task a substantial and stable impairment. These four experiments require a revised interpretation of the effects of fornix transection upon recognition memory and exploration. Particularly they contradict the hypothesis, suggested by previous experiments, that fornix transection produces a defect in discrimination of stimulus familiarity in long-term but not in short-term memory. They suggest rather that fornix transection impairs memory of instrumental responses.

Reversal learning by fornix-transected monkeys.

Experiment 1 examined visual reversal learning and in Experiment 2 monkeys were trained to criterion in a serial reversal set between “FR” and “DRO” response requirements. In both cases impairments were observed in fornix-transected monkeys. These results are discussed in connection with previous findings that in serial reversals damage to the hippocampal system in monkeys causes a deficit in spatial but not in visual learning. A unified account is proposed.

Effects of fornix transection upon associative memory in monkeys: role of the hippocampus in learned action.

Thirty-three monkeys took part in seven experiments designed to elucidate further the effect of fornix transection on learning and memory. In the first experiment the monkeys had to remember whether stimulus objects had previously been paired with reward or no reward, and they had to use this memory to guide choice between stimulus objects at retention tests according to an arbitrary rule which they had learned: to choose objects previously paired with no reward in preference to objects previously paired with reward. Fornix transection produced a severe and permanent impairment in this task. In the second experiment the monkeys also had to remember object-reward associations but the performance rule was more natural: to choose objects previously paired with reward. Here fornix transection had no effect. The third experiment required the monkeys to remember, given a stimulus object, which of two events of equal valence had previously been the outcome of displacing that object. The two events were either a peanut and a sultana or a black penny and a white penny of equal secondary reinforcing value. Performance was unimpaired by fornix transection. The fourth experiment also demonstrated, in a different paradigm, unimpaired recall of sensory events. The fifth experiment demonstrated an impairment following fornix transection in acquisition of simultaneous spatial-visual conditional discriminations; the sixth demonstrated normal learning by fornix-transected monkeys of a successive spatial-visual conditional discrimination and the seventh demonstrated unimpaired acquisition of a simultaneous auditory-visual conditional discrimination. These results, when considered in detail and together, are incompatible with existing hypotheses of hippocampal function. A new hypothesis is discussed.

Recognition Memory after Short Retention Intervals in Fornix-Transected Monkeys

Fornix-transected monkeys were impaired in recognition memory after brief retention intervals for short lists of either colours or spatial positions. The results were contrasted with the existing evidence in human amnesic patients for a neurologically separate, intact short-term memory system.