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M Mishkin

Publications and source records attributed to M Mishkin.

At least 19 recordsLinked to original sources

Serial and parallel processing of tactual information in somatosensory cortex of rhesus monkeys.

1. Selective ablations of the hand representations in postcentral cortical areas 3a, 3b, 1, and 2 were made in different combinations to determine each area's contribution to the responsivity and modality properties of neurons in the hand representation in SII. 2. Ablations that left intact only the postcentral areas that process predominantly cutaneous inputs (i.e., areas 3b and 1) yielded SII recording sites responsive to cutaneous stimulation and none driven exclusively by high-intensity or "deep" stimulation. Conversely, ablations that left intact only the postcentral areas that process predominantly deep receptor inputs (i.e., areas 3a and 2) yielded mostly SII recording sites that responded exclusively to deep stimulation. 3. Ablations that left intact only area 3a or only area 2 yielded substantial and roughly equal reductions in the number of deep receptive fields in SII. By contrast, ablations that left intact only area 3b or only area 1 yielded unequal reductions in the number of cutaneous receptive fields in SII: a small reduction when area 3b alone was intact but a somewhat larger one when only area 1 was intact. 4. Finally, when the hand representation in area 3b was ablated, leaving areas 3a, 1, and 2 fully intact, there was again a substantial reduction in the encounter rate of cutaneous receptive fields. 5. The partial ablations often led to unresponsive sites in the SII hand representation. In SII representations other than of the hand no such unresponsive sites were found and there were no substantial changes in the ratio of cutaneous to deep receptive fields, indicating that the foregoing results were not due to long-lasting postsurgical depression or effects of anesthesia. 6. The findings indicate that modality-specific information is relayed from postcentral cortical areas to SII along parallel channels, with cutaneous inputs transmitted via areas 3b and 1, and deep inputs via areas 3a and 2. Further, area 3b provides the major source of cutaneous input to SII, directly and perhaps also via area 1. 7. The results are in line with accumulating anatomic and electrophysiologic evidence pointing to an evolutionary shift in the organization of the somatosensory system from the general mammalian plan, in which tactile information is processed in parallel in SI and SII, to a new organization in higher primates in which the processing of tactile information proceeds serially from SI to SII. The presumed functional advantages of this evolutionary shift are unknown.

Animals

Massive cortical reorganization after sensory deafferentation in adult macaques.

After limited sensory deafferentations in adult primates, somatosensory cortical maps reorganize over a distance of 1 to 2 millimeters mediolaterally, that is, in the dimension along which different body parts are represented. This amount of reorganization was considered to be an upper limit imposed by the size of the projection zones of individual thalamocortical axons, which typically also extend a mediolateral distance of 1 to 2 millimeters. However, after extensive long-term deafferentations in adult primates, changes in cortical maps were found to be an order of magnitude greater than those previously described. These results show the need for a reevaluation of both the upper limit of cortical reorganization in adult primates and the mechanisms responsible for it.

Afferent Pathways

Dissociation of object and spatial visual processing pathways in human extrastriate cortex.

The existence and neuroanatomical locations of separate extrastriate visual pathways for object recognition and spatial localization were investigated in healthy young men. Regional cerebral blood flow was measured by positron emission tomography and bolus injections of H2(15)O, while subjects performed face matching, dot-location matching, or sensorimotor control tasks. Both visual matching tasks activated lateral occipital cortex. Face discrimination alone activated a region of occipitotemporal cortex that was anterior and inferior to the occipital area activated by both tasks. The spatial location task alone activated a region of lateral superior parietal cortex. Perisylvian and anterior temporal cortices were not activated by either task. These results demonstrate the existence of three functionally dissociable regions of human visual extrastriate cortex. The ventral and dorsal locations of the regions specialized for object recognition and spatial localization, respectively, suggest some homology between human and nonhuman primate extrastriate cortex, with displacement in human brain, possibly related to the evolution of phylogenetically newer cortical areas.

Adult

Transient impairment of recognition memory following ibotenic-acid lesions of the basal forebrain in macaques.

To assess the contributions of the basal forebrain cholinergic nuclei to visual recognition memory in macaques, we compared the effects of lesions of (a) the nucleus basalis of Meynert, (b) the medial septal and diagonal band nuclei, and (c) all nuclei combined on performance of delayed nonmatching-to-sample with trial-unique stimuli. Whereas monkeys with the separate lesions did not differ from each other or from normal control animals, those with combined lesions showed a significant impairment. With time and extended practice, however, the performance of the animals with combined lesions recovered to normal levels. During the recovery period, these monkeys showed an initially increased sensitivity to scopolamine that later dissipated, at which time they also failed to show the improvement that follows physostigmine administration in normal animals. Postmortem assessment of cortical choline acetyltransferase activity revealed that only the group with combined lesions had significant depletion of this enzyme. The results suggest that (1) the basal forebrain cholinergic system participates in mnemonic processes in primates and that (2) extensive damage to this system is necessary before impairments in recognition memory, even transient ones, can be observed.

Acetylcholinesterase

The role of the inferior prefrontal convexity in performance of delayed nonmatching-to-sample.

Findings in an earlier study (Bachevalier, J. and Mishkin, M. Behav. Brain Res. 20, 249-261, 1986) indicated that ventromedial prefrontal cortex, which receives thalamic projections from the limbo-diencephalic system, is critical for visual recognition; whereas the dorsolateral prefrontal cortex, which receives no such thalamic projections, makes little or no contribution to this type of memory. In the present study, we examined the role in recognition of another prefrontal area outside the thalamic projection zone of the limbo-diencephalic system, namely, the inferior prefrontal convexity. In the first experiment, monkeys with lesions of this cortex (Group IC) were found to be impaired in relearning delayed nonmatching-to-sample (DNMS), but not on the subsequent DNMS performance test in which memory demands were greatly increased. In a second experiment, monkeys with combined lesions of the inferior and dorsolateral prefrontal cortex (Group LAT) were also found to be impaired in relearning DNMS, but in this case they were impaired, in addition, on the subsequent performance test. Neither group (IC or LAT) showed retardation in acquiring visual discrimination habits. Analysis of the DNMS behavior of both groups suggested that their deficits on this task were due not to a loss in recognition memory, but to various forms of perseverative interference. The results support the view that the inferior prefrontal convexity, like the dorsolateral prefrontal cortex, lies outside the limbo-diencephalic memory system not only anatomically but also functionally.

Animals

Comparison of the effects of scopolamine administered before and after acquisition in a test of visual recognition memory in monkeys.

The effect of scopolamine on visual recognition memory in rhesus monkeys was assessed with a delayed nonmatching-to-sample task employing trial-unique stimuli. During the acquisition phase, 40 sample stimuli were presented sequentially. During the test phase, these same stimuli were presented in the reverse order, each paired with a novel stimulus. The animal was rewarded for choosing the novel stimulus in each pair. Two versions of this design were used. In Task 1, scopolamine (10.0 or 17.8 micrograms/kg) was administered 20 min prior to acquisition, which was followed immediately by the test phase. In Task 2, the drug was administered immediately after acquisition, which was followed 20 min later by the test phase. Performance was impaired in a dose-related manner in Task 1, but not at all in Task 2, indicating that the effects of scopolamine on performance cannot be attributed to an impairment either in the retrieval of stored information or in the attentive or perceptual discriminative processes needed for such retrieval, or, by implication, for storage. In addition, the forgetting curves for scopolamine in Task 1 were parallel to those of the control sessions; i.e., the curves did not diverge with increasing delay intervals, indicating that scopolamine did not increase the rate of forgetting. Taken together, the results suggest that scopolamine interferes selectively with the initial storage of the information to be remembered.

Animals

Visual impairments in macaques following inferior temporal lesions are exacerbated selectively by additional damage to superior temporal sulcus.

The present study examined the behavioural effects of removing the inferior temporal cortex (area TE) either on its own or in combination with the adjacent fundus and upper bank of the superior temporal sulcus (area STP). Comparisons with preoperative behaviour showed that the addition of superior temporal sulcal damage led to an increase in visual components of the Klüver-Bucy syndrome, i.e. an increased tendency to touch and examine objects coupled with a decrease in emotional reactivity, but no excessive orality, changes in food preference, or coprophagia. No group differences were found in the learning of 3 pattern discriminations, but the animals with additional superior temporal sulcal lesions were more impaired than the others on 3 colour discriminations, successive reversals of an object discrimination, and a learning-set task. These findings indicate that STP provides an important route, independent of the route via TE, by which visual information can reach limbic structures to evoke affective responses and contribute to visual learning.

Amygdala

Picture recognition vs. picture discrimination learning in monkeys with medial temporal removals.

Three monkeys with complete ablations of temporal-lobe limbic structures and three unoperated controls were compared in an automated testing apparatus for their ability to remember pictures presented between 1 and 180 seconds previously, as well as to learn picture discriminations in which successive trials with a given pair were separated by either 20 seconds or 24 hours. The operated animals were not impaired in picture discrimination learning under either condition and they were not impaired in picture recognition memory up to about 10 seconds. At 10 seconds and beyond, however, the operated animals showed rapid deterioration of picture memory. The results demonstrate that the limbic system's selective contribution to learning and retention uncovered initially with objects applies equally to pictures, this contribution being essential for recognition memory but not for discrimination habits. The results demonstrate further that, as in humans, temporal-lobe limbic structures are essential for recognition only when the retention test exceeds the immediate memory span of a few seconds.

Animals

Age and sex differences in the effects of selective temporal lobe lesion on the formation of visual discrimination habits in rhesus monkeys (Macaca mulatta).

Three-month-old infant monkeys with neonatal ablations of either cortical area TE or the amygdala and hippocampus and age-matched normal infants were trained in a concurrent object discrimination task with 24-hr intertrial intervals. Neonatal area TE lesions yielded a transient deficit in visual habit formation, present in the female monkeys only, whereas the same lesions in adult monkeys yielded a severe and long-lasting deficit in both males and females. Although pointing to a greater neural compensation for the early loss as compared with the later loss of cortical area TE, the results also corroborate a recent suggestion (Bachevalier, Hagger, & Bercu, 1989) that, at 3 months of age, area TE is more fully functional in females than in males. Neither early nor late amygdalohippocampal lesions impaired the ability to form visual discrimination habits, strengthening the proposal that the habit system uses a corticononlimbic circuit.

Aging

Discrimination learning alters the distribution of protein kinase C in the hippocampus of rats.

Protein kinase C (PKC), an enzyme that plays an essential role in eukaryotic cell regulation (Nishizuka, 1988; Huang et al., 1989), is critical to memory storage processes both in the marine snail Hermissenda crassicornis and in the rabbit (Alkon et al., 1988; Bank et al., 1988; Olds et al., 1989). Specifically, activation of PKC mimics neurobiological correlates of classical conditioning in both Hermissenda and the rabbit, and the distribution of the enzyme within the rabbit hippocampus changes after Pavlovian conditioning. Here, we report that the amount of PKC, as assayed by specific binding of 3H-phorbol-12,13-dibutyrate (3H-PDBU), decreased significantly within the hippocampal CA3 cell region in rats trained to solve a water maze task either by cognitive mapping or by visual discrimination strategies, but not in control rats. Furthermore, hippocampal lesions interfered with acquisition of both of these tasks. We interpret these findings to support the conclusion that distributional changes of PKC within the mammalian hippocampus play a crucial role in memory storage processes.

Animals

Mnemonic and neuropathological effects of occluding the posterior cerebral artery in Macaca mulatta.

To investigate experimentally the mnemonic and neuropathological effects of blockage of the posterior cerebral arteries (PCA), a cerebrovascular accident that can lead to global anterograde amnesia in humans, we permanently occluded these arteries bilaterally in six monkeys and then evaluated their performance on a visual recognition task, after which we assessed the extent of their ischemic infarcts. The latter showed substantial individual variation, ranging from almost no damage in one case to massive unilateral injury of both the ventromedial o occipitotemporal cortex and hippocampal formation in another. In the four remaining cases, however, the infarcts fell within a narrow range, being confined almost entirely to the hippocampal formation and parahippocampal gyrus, and then only to restricted portions of these structures, unilaterally in one case, and bilaterally in the three others. Performance on the recognition task was related to the presence and bilaterality of the hippocampal injury. Thus, the case without any hippocampal damage performed at a rate equal to that of normal controls; the case with unilateral hippocampal damage was mildly impaired; and the three cases with bilateral infarctions, involving between 20 and 55% of the hippocampal formation, showed substantial impairment, with scores averaging 20% below those of normal controls. The only subfields of the hippocampus damaged in common in these cases were CA1 and CA2. Paradoxically, the memory loss found in these three animals with only partial bilateral hippocampal damage was significantly greater than that found in animals with total bilateral ablation of the hippocampal formation, whose scores averaged only 10% below those of normal controls. Possible explanations for this extremely puzzling outcome are proposed.

Amnesia

Improved recognition memory in monkeys following naloxone administration.

The effects of naloxone on visual recognition were evaluated in five macaques trained in delayed nonmatching-to-sample with trial-unique objects. In four of the five monkeys, naloxone yielded an inverted U-shaped dose-effect curve. For each of these four animals, as well as for all five animals as a group, at least one dose within a narrow range (0.32-3.2 mg/kg) produced a significant increase in the number of objects correctly recognized. Lower doses had little effect, while the highest dose (10.0 mg/kg) tended to disrupt performance.

Animals

Dissociation of the effects of inferior temporal and limbic lesions on object discrimination learning with 24-h intertrial intervals.

Monkeys with bilateral ablations of the inferior temporal cortical area TE were trained on a visual discrimination task thought to measure non-cognitive habit formation. The task consisted of 20 object discriminations presented concurrently, but at the rate of only one trial on each per day; successive trials on a given discrimination were thus separated by 24-h intertrial intervals. Performance on this task by the animals with TE lesions was compared to that of both normal control monkeys and monkeys that had sustained bilateral removals of the amygdala and hippocampus. In contrast to the latter animals, which learned the 24-h intertrial interval task about as quickly as the normal controls, monkeys with area TE removals were markedly impaired. Taken together with earlier findings demonstrating that ablation of area TE impairs visual recognition memory, the present results suggest that area TE contributes not only, like limbic structures, to a cognitive memory system, but also, unlike limbic structures, to a non-cognitive habit system. Evidence is reviewed suggesting that this latter system may involve a corticostriatal circuit.

Animals

Lesion-induced plasticity in the second somatosensory cortex of adult macaques.

We have reported that elimination of the representation of any body part in the primary (i.e., postcentral) somatosensory cortex of the adult macaque selectively eliminates the representation of that same body part in the second somatosensory area SII. We now report that, although removal of the entire postcentral hand representation does indeed leave the SII hand representation unresponsive to somatic stimulation initially, 6-8 weeks later this cortex is no longer silent. Instead, most or all of the region that had been vacated by the hand representation is now found to be occupied by an expanded foot representation. This massive somatotopic reorganization, involving more than half the areal extent of SII, exceeds that previously observed in the postcentral cortex after peripheral nerve damage and may reflect a greater capacity for reorganizational changes in higher order than in primary sensory cortical areas.

Animals

A selective mnemonic role for the hippocampus in monkeys: memory for the location of objects.

Monkeys were trained preoperatively on a one-trial learning task in which they were required to associate in memory a novel object and the place in which it had just appeared. After learning the task to a level of 80% correct responses, they received bilateral ablations of either the hippocampal formation or the amygdaloid complex. The monkeys with amygdalectomy showed a small drop in performance initially but then regained their preoperative level. By contrast, the monkeys with hippocampectomy dropped to near-chance levels of performance and remained there throughout postoperative testing. Both groups performed at better than 90% correct responses on a test of recognition memory. These results, taken together with earlier work, suggest that although the hippocampus and amygdala appear to participate equally in object recognition, only the hippocampus is critical for the rapid formation of object-place associations.

Animals

Gradients of protein kinase C substrate phosphorylation in primate visual system peak in visual memory storage areas.

Two protein kinase C (PKC) substrates of 50 and 81 kDa display topographical gradients in 32P-incorporation along the occipitotemporal visual processing pathway in rhesus monkey cerebral cortex. The 50 kDa protein appears to be homologous to protein F1 from rat (47 kDa) on the basis of isoelectric point, two-dimensional phosphopeptide maps, and kinase specificity, while the 81 kDa protein is probably the same as a previously described PKC substrate. The phosphorylation of protein F1 and 81 kDa was significantly higher in temporal regions of the occipitotemporal pathway, which have been implicated in the storage of visual representations, than in occipital regions, which appear to be less important for visual memory functions. These results suggest that the PKC phosphorylation system, which has been related previously to changes in neural plasticity, plays a progressively greater role in later stages of visual processing, and that this role may involve the storage of visual information in inferotemporal cortical areas.

Animals

Physiological evidence for serial processing in somatosensory cortex.

Removal of the representation of a specific body part in the postcentral cortex of the macaque resulted in the somatic deactivation of the corresponding body part in the second somatosensory area. In contrast, removal of the entire second somatosensory area had no grossly detectable effect on the somatic responsivity of neurons in the postcentral cortex. This direct electrophysiological evidence for serial cortical processing in somesthesia is similar to that found earlier for vision and, taken together with recent anatomical evidence, suggests that there is a common cortical plan for the processing of sensory information in the various sensory modalities.

Animals

Effects of scopolamine and physostigmine on recognition memory in monkeys with ibotenic-acid lesions of the nucleus basalis of Meynert.

Monkeys with bilateral ibotenic-acid lesions of the nucleus basalis of Meynert, an area rich in cholinergic neurons that innervate the cerebral cortex, were compared with unoperated control monkeys on a recognition memory task. Although animals with large lesions had substantial reductions of cortical choline acetyltransferase activity, none showed impairment in the task. Lesion effects were observed, however, when performance was assessed following administration of a muscarinic receptor blocker (scopolamine) or a cholinesterase inhibitor (physostigmine). Although scopolamine produced dose-related impairments in both groups, this effect was greater in the experimental animals. Conversely, whereas physostigmine produced modest improvement in performance in the control group, no such improvement was observed in the experimental animals. The altered sensitivity to the mnemonic effects of cholinergic agents in the experimental group suggests that the cholinergic neurons of the nucleus basalis of Meynert contribute to recognition memory.

Acetylcholinesterase