SUMMARIES OF RESEARCH PROJECTS October l, l997 to present Project #1: Neural mechanisms of stimulus memory and habit formation Collaborators: R.C. Saunders, Ph.D. LN, NIMH L. Malkova, Ph.D., Georgetown University Medical School F. Vargha-Khadem, Ph.D., Institute of Child Health, University College London D.G. Gadian, Ph.D., Institute of Child Health, University College London A.D. Baddeley, University of Bristol Summary  The essential circuit for both item and associative stimulus recognition in any given sensory modality (or across modalities) consists of the relevant cortical sensory processing stream(s), the medial temporal periallocortex (i.e. parahippocampal, perirhinal, and entorhinal cortices), the ventromedial prefrontal cortex, and the magnocellular division of the medial dorsal nucleus of the thalamus. Associative recall, on the other hand, appears now to be organized hierarchically; thus, whereas context-free recall, or fact memory, also seems to depend primarily on the above basic memory circuit, context-rich recall, or event memory, seems to depend in addition on a higher-order circuit superimposed on the basic one and consisting of the hippocampus, mamillary body, anterior thalamic nuclei, and cingulate cortex. That item recognition at least does not depend on the higher-order memory circuit is supported by new evidence obtained in Jon (reported on initially in Science 277: 376-380, 1997) who has seemingly selective bilateral hippocampal pathology induced by a neonatal hypoxic/ischaemic insult. On standardized memory tests allowing quantitative assessment, Jon's recognition scores were at or above the 50th percentile whereas his recall scores fell below the 1st percentile. That associative recognition also does not depend on the higher-order memory circuit (but does require the basic circuit) is supported by new evidence obtained in monkeys. These results indicate that the ability to form one-trial object-place associations is unaffected by selective, excitotoxic damage to the hippocampus, and yet is severely impaired by ablation of the underlying parahippocampal cortex. Project #2: Cerebral mechanisms of auditory perception and memory Collaborators:J.B. Fritz, Ph.D., LN NIMH A. Poremba, Ph.D., LN NIMH R.C. Saunders, Ph.D., LN NIMH J.P. Rauschecker, Ph.D., Georgetown University Medical School B. Tian, Ph.D., Georgetown University Medical School Summary  Monkeys were preoperatively trained on an auditory version of recognition memory with a stimulus set of 1000 complex sounds, each lasting 1-2 sec, and then examined with variable recognition delays (between a sample and a test stimulus) of 5-50 sec. Postoperative results indicate that perirhinal/entorhinal (i.e. rhinal) lesions, which are known to produce severe impairment in both visual and tactile recognition memory, have no effect on the auditory version of this mnemonic ability. The finding points to an unexpected difference in the organization of sensory-limbic interaction underlying stimulus memory in the different exteroceptive modalities. Selective responses of neurons in the auditory lateral belt areas, which receive input from the primary auditory areas, seem to be due mainly to temporal and spectral integration across frequencies rather to differences in frequency, per se. To test this notion further, we used a standard set of monkey vocalizations and their components as stimuli. We have found some lateral-belt neurons that display temporal combination sensitivity (in which the response to the whole monkey call is greater than the sum of the responses to individual components), other lateral-belt neurons that show temporal suppression (in which the response to one component of the call is reduced when it is preceded or followed by another component of the call), and still other neurons that show both types of nonlinear interaction. The proportion of neurons showing these complex selectivities is greater in the lateral belt than in the primary auditory areas, supporting the existence of an auditory processing hierarchy within the superior temporal gyrus. Project #3: Neural substrates of cognitive and socioemotional development Collaborators:L. Malkova, Ph.D., Georgetown University Medical School J. Bachevalier, Ph.D., University of Texas Medical School, Houston. Summary  Earlier we had assessed visual recognition in monkeys after neonatal damage either to the entire medial temporal region or to cortical visual area TE, both of which are known to be essential for this mnemonic ability in adult monkeys. The results indicated substantial functional sparing after the neonatal cortical but not after the neonatal medial temporal removals. These findings, together with those of follow-up studies with larger lesions of extrastriate visual cortex, suggest that, during infancy, visual recognition functions are widely distributed throughout many visual cortical areas and that they become critically dependent on (i.e. localized to) area TE only after cortical maturation. In a new follow-up study, we have examined the effects of neonatal medial temporal removals limited to the perirhinal/entorhinal (i.e. rhinal) cortices, which is known from lesion studies in adult monkeys to be the critical medial temporal substrate for visual recognition memory. Our findings indicate that rhinal lesions in neonates, just like rhinal lesions in adults, produce a long-lasting impairment of visual recognition that is nearly as severe as that produced by removal of the entire medial temporal region. Thus, unlike the mnemonic functions of cortical visual area TE, those of the rhinal cortex cannot be assumed by any other region even when the damage occurs neonatally. Apparently, the functions of limbic or periallocortex are more firmly fixed at birth than those of neocortex. Project #4: Pharmacology of stimulus memory and habit formation Collaborators:Y. Tang, Ph.D., LN NIMH T.G. Aigner, Ph.D., DBR NIDA Summary  Evidence from our studies on the effects of systemic injections of pharmacological agents in behaving monkeys has led to the proposal that the formation of stimulus memories depends on interaction between the cholinergic and glutamatergic systems. More specifically, our evidence suggests that the critical event for storage of the trace or representation of a stimulus is the potentiation exerted by activation of the cholinergic muscarinic receptor on activity mediated by the glutamatergic NMDA receptor. To test this hypothesis, we have been examining the effects of microinjecting pharmacological agents directly into the perirhinal cortex, which is known from lesion studies to be the most critical area in the temporal lobe for stimulus recognition. Our results thus far have shown that, like systemic injections of a cholinergic muscarinic receptor antagonist (scopolamine), microinjecting this drug into perirhinal cortex impairs recognition memory. By contrast, recognition memory is unaffected by either systemic or perirhinal injections of dopaminergic receptor antagonists (e.g. haloperidol)). We have also demonstrated that, like systemic injections of an NMDA receptor antagonist (MK-801), perirhinal microinjections of such an antagonist (D-AP5) impairs recognition memory. Again by contrast, recognition memory is unaffected by perirhinal injections of a kainate/AMPA receptor antagonist (CNQX). These results provide preliminary support not only for the hypothesis regarding an interaction between muscarinic and NMDA receptor activation, but also for the notion that such interaction occurs within the neurons of the perirhinal cortex.

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The Laboratory of Neuropsychology is part of the Division of Intramural Research Programs is within the National Institute of Mental Health (NIMH) is a part the National Institutes of Health (NIH), is a component of the U.S. Department of Health and Human Services.